Apparatus for extracorporeal blood treatment ii

ABSTRACT

An extracorporeal blood treatment apparatus is provided comprising a filtration unit (2) connected to a blood circuit (17) and to a dialysis fluid circuit (32), a preparation device (9) for preparing and regulating the composition of the dialysis fluid; a control unit (12) is configured for determining or receiving a proposed value (prop.value; Cprop.value) of a sodium concentration for the dialysis fluid in the dialysis supply line (8) and to determine a set value (fsetvalue; Cse tvalue) for the sodium concentration in the dialysis fluid as a function of the proposed value (prop.value; Cprop.value). For at least an interval of proposed values for the sodium concentration, the control unit (12) is configured to determine the set value so that the set value is different from the proposed value (prop.value; cprop.value) and so that distinct set values are determined from distinct proposed values. The set value is biased towards a predetermined pivot value that represents e.g. the average sodium concentration in the blood of a population and may not be outside a reference range.

TECHNICAL FIELD

The present invention relates to an apparatus for extracorporeal bloodtreatment and a method for controlling the extracorporeal bloodtreatment apparatus.

In particular, the invention may be used for regulating the conductivityof a dialysis fluid during a hemodialysis or hemodiafiltrationtreatment.

In more detail, the apparatus and the method are particularly adaptedfor properly regulating the concentration of sodium in the dialysisfluid, particularly to run a more physiological isotonic or isonatremicor isonatrikalemic dialysis treatment.

BACKGROUND OF THE INVENTION

The kidneys fulfil many functions, including the removal of water, theexcretion of catabolites (or waste from the metabolism, for example ureaand creatinine), the regulation of the concentration of the electrolytesin the blood (e.g. sodium, potassium, magnesium, calcium, bicarbonates,phosphates, chlorides) and the regulation of the acid/base equilibriumwithin the body, which is obtained in particular by the removal of weakacids (phosphates, monosodium acids) and by the production of ammoniumsalts.

In individuals who have lost the use of their kidneys, since theseexcretion and regulation mechanisms no longer work, the body accumulateswater and waste from the metabolism and exhibits an excess ofelectrolytes, as well as, in general, acidosis, the pH of the bloodplasma shifting downwards, below 7.35 (the blood pH normally varieswithin narrow limits of between 7.35 and 7.45).

In order to overcome renal dysfunction, resort is conventionally made toa blood treatment involving extracorporeal circulation through anexchanger having a semipermeable membrane (dialyzer) in which thepatient's blood is circulated on one side of the membrane and a dialysisfluid, comprising the main electrolytes of the blood in concentrationsclose to those in the blood of a healthy subject, is circulated on theother side.

Furthermore, a pressure difference is created between the twocompartments of the dialyzer which are delimited by the semipermeablemembrane, so that a fraction of the plasma fluid passes byultrafiltration through the membrane into the compartment containing thedialysis fluid.

The blood treatment which takes place in a dialyzer as regards wastefrom the metabolism and electrolytes results from two mechanisms ofmolecular transport through the membrane.

On the one hand, the molecules migrate from the liquid where theirconcentration is higher to the liquid where their concentration islower. This is diffusive transport.

On the other hand, certain catabolites and certain electrolytes areentrained by the plasma fluid which filters through the membrane underthe effect of the pressure difference created between the twocompartments of the exchanger. This is convective transport.

Three of the abovementioned functions of the kidney, namely the removalof water, the excretion of catabolites and the regulation of theelectrolytic concentration of the blood, are therefore performed in aconventional blood treatment device by the combination of dialysis andblood filtration (this combination is referred to as hemodialysis).

Moreover, sodium is the main ionic solute of extracellular volume. Fromliterature search and according to the main opinion leaders in thedialysis field, the determination of dialysis fluid sodium concentrationto be used during the dialysis treatment appears as one of the majorchallenges of dialysis prescription.

The dialysis fluid sodium concentration significantly affects the sodiumbalance and the intracellular hydration of the patient with implicationson hemodialysis tolerance and also long term patient survival.

Hypertonic dialysis fluid sodium prescription will result in a positivesodium balance followed by a water shift from the intracellular toextracellular compartment. The intracellular dehydration increasesvasopressin release and provokes thirst with the consequence of agreater inter-dialytic weight gain and hypertension.

On the contrary, a dialysis fluid sodium concentration that is too low(i.e., hypotonic) will provoke a negative sodium gradient with a watershift in the intracellular compartment, which is responsible forintra-dialytic cramps, headache, hypovolemia and risk of hypotension.

One of current opinions is the idea that sodium balance should bemaintained substantially null during a dialysis treatment: this is basedon the so-called “sodium set point” theory, according to which bothhealthy subjects and dialysis patients tend to maintain a stableextra-cellular sodium concentration.

As above mentioned, sodium is removed during dialysis through convectionand diffusion. The main sodium removal process during dialysis isconvective. If we assume that the ultrafiltrate fluid is basicallyisotonic, convection does not change the tonicity of the extracellularfluid.

There is a need to help the physician to prescribe a correct and“physiological” dialysis fluid composition to treat the patient.

Moreover, a second need is to have a bio-sensing-based therapy which iseasy to use and designed also for operators not very skilled or workingin crowded and very busy dialysis rooms.

To at least partly solve the above mentioned drawbacks, document U.S.Pat. No. 4,508,622 teaches a dialysis device in which the electrolytecomposition of the untreated and treated fluids routed through thedialyzer may be determined and the composition of the dialysis solutionadapted to the patient's requirements.

A first electrolyte detector (conductivity cell) is provided upstream ofthe dialyzer and a second electrolyte detector (conductivity cell) isprovided downstream of the dialyzer. Each detector is coupled to areadout element through which both of the values of the dialysissolution may be observed and eventually controlled. In more detail, theapparatus according to U.S. Pat. No. 4,508,622 consists essentially of aunit for production of the dialysis solution and a dialyzer connected tothe unit and followed downstream by a pump to produce a vacuum in thedialyzer on the side of the dialysis fluid. The detector mountedupstream of the dialyzer, and connected with a control unit, measuresthe conductivity of the total dialysis solution.

A second detector is mounted downstream of dialyzer and is connectedwith a comparator which is, in turn, connected to a differentiationunit. A control signal is provided by the differentiation unit tocontrol unit if there is a difference in the differentiation unit thatdeviates from the predetermined nominal value.

During dialysis fluid circulation, if detector generates a signal to theevaluation unit and subsequently to the differentiation unit whichdeviates by a certain amount from the signal generated by detector,i.e., a difference in value appears which deviates from thepredetermined value for differentiation unit, the difference unitactivates the control unit, which in turn switches concentrate pump onor off as a function of the higher or lower concentration in thedialysis solution to be produced. A treatment in which the dialysisfluid has the same conductivity of the blood and of the spent dialysisfluid, is one of the described implementations.

However, the dialysis fluid and the blood reach the same conductivityafter a certain time lapse which clearly affects the pre-dialytic plasmasodium content. Therefore, the method described in U.S. Pat. No.4,508,622 in not properly an ‘isoconductive’ dialysis treatment.

In any case, ‘isoconductive’ dialysis has been shown to lead toundesired sodium loading in the patient.

Moreover, the prior art devices include dialysis apparatus wherein theconductivity of dialysis fluid is controlled in order to reach a desiredpost-dialysis plasmatic conductivity, i.e. conductivity (or sodiumconcentration) of the patient's blood at the end of the dialysistreatment.

It is known, for example from EP 1389475, a dialysis apparatus providedwith a conductivity system that computes the dialysis fluid conductivity(corresponding to the dialysis fluid sodium concentration) from periodicmeasurements of the sodium blood concentration allowing the sodium levelof the patient to reach a prescribed end-of-session value.

This dialysis apparatus includes a bag and a pump for infusing a patientwith an infusion solution containing sodium at a determined and knownconcentration.

A structure for determining the sodium concentration [Na⁺]_(dial) of thedialysis fluid is also provided so that the patient's body tends towardsa desired sodium concentration [Na⁺]_(des), as a function of thedialysance D for sodium of the dialyser, of the desired sodiumconcentration [Na⁺]_(des) inside the patient's body, of the infusionflow rate and of the sodium concentration [Na⁺]_(sol) of the infusionsolution.

A control unit drives the pump for regulating the sodium concentrationof the dialysis fluid such that this concentration is equal (tendstowards) to the determined concentration [Na⁺]_(dial).

As previously mentioned, one of the problems of the dialysis apparatusof the discussed prior art is presently the choice of the appropriatepost-dialysis plasmatic conductivity target.

With the methods described, for example in EP 547025 or in EP 920877, itis possible to determine the plasma conductivity and thereby to properlyregulate the dialysis fluid preparation section.

The described system however changes the blood conductivity and tonicitysince the dialysis fluid enters into contact and exchange significantlywith blood before a plasma conductivity calculation; the effect onplasma conductivity is in an amount proportional to the differencebetween blood and dialysis fluid conductivities.

Document U.S. Pat. No. 8,182,692 describes a dialysis apparatusproviding a treatment in which a dialysis fluid having a sodiumconcentration substantially equal to the estimated current sodiumconcentration in the patient's blood is performed by placing thedialysis fluid in communication with the patient's blood across thesemi-permeable membrane to perform a dialysis treatment on the patient'sblood without substantially altering the sodium concentration of thepatient's blood during the performance of the dialysis treatment.

In more detail, a solution supply device, containing aconductivity-testing solution, is selectively placed in communicationwith dialyzer and the blood flowing therein.

According to this patent, any subject, including hemodialysis patients,has a set level of sodium in his body, referred to as the “set point.”The set point of a subject tends to remain relatively constant, andsodium levels deviating too far from the set point may cause discomfortto the subject. Given the above, the method of the prior art includescausing blood to flow through blood conduit of the dialyzer and flowingthe conductivity-testing solution in the opposite direction through thedialyzer.

Conductivity detectors measure the conductivity of conductivity-testingsolution as the solution enters and exits dialyzer. Conductivity-testingsolution is formulated such that electrically conductive solutes otherthan sodium in the patient's blood have little or no effect on theconductivity measurements of conductivity-testing solution.

According to U.S. Pat. No. 8,182,692, due to the closely matchedconcentrations of electrically conductive solutes, such as phosphate,sulfate, bicarbonate, potassium, calcium, and magnesium, inconductivity-testing solution and in the patient's blood, littlediffusion of those electrically conductive solutes occurs acrossmembrane. Consequently, the conductivity measurements ofconductivity-testing solution is closely correlated with the level ofsodium in the patient's blood.

Therefore, conductivity-testing solution is exclusively used toaccurately determine the level of sodium in the patient's blood as afunction of the change in conductivity across dialyzer of theconductivity-testing solution.

Control unit then determines the level of sodium in the patient's bloodas a function of the measured conductivity values.

After determining the concentration of sodium in the patient's blood,dialysis fluid may be prepared to include a concentration of sodium thatis substantially equal to the concentration of sodium determined toexist in the patient's blood.

Moreover, US2012/018379 discloses an apparatus and a method for thedetermination and regulation of the concentration of one dissolvedsubstance (e.g. sodium) in a dialysis fluid circuit of a hemodialysismachine.

The user presets the sodium regulation range before the start of thedialysis using an estimated value for the dialysis fluid sodium requiredto achieve the isonatremic state or a lab measurement of the patientsodium or a value determined by the regulation from earlier treatments.In addition, the distribution volume of the patient is input for theapplication of the model for the correction of the diffusive balance.Furthermore, the initial concentrations of bicarbonate and potassium inthe patient are set. They come from an analysis by means of a blood gasanalyzer before the start of the dialysis treatment.

After the start of the treatment, the dialysis fluid flow and theconductivity are determined upstream and downstream of the dialyzer anda calculation of the updated current bicarbonate and potassiumconcentration in the patient takes place with it being assumed that thepotassium clearance corresponds to the sodium clearance and that thebicarbonate clearance corresponds to 70% of the sodium clearance. Thesodium clearance from the blood flow is estimated until the presence ofthe first clearance measurement.

The calculation of the conductivity balance and of the correction termfor the ion exchange and thus for the sodium balance then takes placefrom these data.

The conductivity of fluids measured upstream and downstream, the sodiumbalance and the correction term for the dialysate conductivitydownstream of the dialyzer are then the input values for the sodiumregulation. The desired conductivity thus determined is finallyconverted into a desired value for the dialysis fluid sodium whiletaking account of the composition of the dialysis concentrate and thispreset value is transmitted to a metering unit for dialysis fluidpreparation.

Notably, patients' plasma sodium vary considerably, both betweenpatients and within a single patient. Indeed, for a big patient group,the average pre-dialysis plasma sodium concentration is approximately138 mmol/l. However, patients may have pre-dialysis plasma sodium in therange 130-143 mmol/l (or even lower or higher). With the exception ofblood glucose causing low plasma sodium, presently the sources of thisvariability are not fully understood. Possibly, the variability of anindividual patient may be due to simply drinking a bit more or a bitless than otherwise mandated by the sodium intake (which governsthirst). In some cases, particularly in presence of high deviations fromthe average plasma sodium concentration, isonatremic (or isotonic orisonatrikalemic) treatments may not be the best treatment option.

Finally, EP 2377563 discloses a dialysis apparatus comprising a bloodtreatment unit with an online preparation device for preparing adialysis fluid containing sodium and comprising a dialysis preparationsection for regulating the concentration of sodium in the dialysisfluid. The blood circuit is configured to circulate extracorporeal bloodthrough the blood chamber; control means determines a valuerepresentative of the sodium concentration in the blood and areprogrammed for driving the dialysis preparation section as a function ofthe determined plasma sodium value, such that the substanceconcentration in the dialysis fluid tends towards: (i) the determinedconcentration of said substance in the blood if the determinedconcentration of said substance in the blood is greater than a minimumthreshold and less than a maximum threshold; (ii) the minimum thresholdif the determined concentration of said substance in the blood is lessthan the minimum threshold; (iii) the maximum threshold if thedetermined concentration of said substance in the blood is greater thanthe maximum threshold.

The plasma sodium content is determined by measuring the inlet andoutlet conductivities of the dialysis fluid upstream and downstream thedialyzer, by then changing the conductivity upstream the filter by aprefixed step and measuring a second time the inlet and outletconductivities of the dialysis fluid upstream and downstream thedialyzer with the modified conductivity value.

SUMMARY

A general aim of the present invention is providing an extracorporealblood treatment apparatus able to automatically perform a proper settingof the dialysis fluid content of a substance, particularly an ionicsubstance, present in the blood as well.

In detail it is an aim of the present invention to provide anextracorporeal blood treatment apparatus with a proper tool helping thephysician to prescribe a “physiological” dialysis fluid composition,particularly to safely run an isotonic, isonatremic or isonatrikalemicdialysis treatment.

It is an aim of the present invention to provide an extracorporeal bloodtreatment apparatus configured for identifying cases for which isotonic,isonatremic or isonatrikalemic dialysis treatments may not be the besttreatment option providing a corresponding more physiological set valuefor the dialysis fluid conductivity.

A further aim of the invention is to make available an extracorporealblood treatment apparatus provided with a selectable biosensing-basedtherapy which is easy to use and designed for not skilled operators orusers working in crowded and busy dialysis rooms.

It is an aim of the invention to provide an extracorporeal bloodtreatment machine configured to automatically perform a proper automaticsetting of the dialysis fluid conductivity.

A further aim of the invention is to make available a dialysis apparatusable to provide an automated delivery and control of the dialysisprescription, particularly in order to restore at each dialysis sessionthe proper sodium-water equilibrium to the patient.

At least one of the above-indicated aims is attained by an apparatus anda corresponding method as in one or more of the appended claims, takensingly or in any combination.

According to a first independent aspect an apparatus for extracorporealblood treatment is provided, comprising:

-   -   a filtration unit (2) having a primary chamber (3) and a        secondary chamber (4) separated by a semi-permeable membrane        (5);    -   a blood withdrawal line (6) connected to an inlet of the primary        chamber (3),    -   a blood return line (7) connected to an outlet of the primary        chamber (3), said blood lines being configured for connection to        a patient cardiovascular system;    -   a dialysis supply line (8) connected to an inlet of the        secondary chamber (4);    -   a dialysis effluent line (13) connected to an outlet of the        secondary chamber (4);    -   a preparation device (9) for preparing a dialysis fluid        connected to said supply line (8) and comprising regulating        means (10) for regulating the composition of the dialysis fluid,    -   a control unit (12) connected to the regulating means (10) and        programmed for obtaining a proposed value (        _(prop.value); c_(prop.value)) of a first parameter for the        dialysis fluid in the dialysis supply line (8), the first        parameter being chosen in the group including a conductivity for        the dialysis fluid, a conductivity-related parameter for the        dialysis fluid, a concentration of at least a substance for the        dialysis fluid, a concentration-related parameter of at least a        substance for the dialysis fluid, said control unit (12) being        configured for determining a set value (        _(setvalue); c_(setvalue)) for the first parameter as a function        of the proposed value (        _(prop.value); c_(prop.value)) for the first parameter, wherein,        for at least an interval of proposed values for the first        parameter, the control unit (12) is configured to determine the        set value so that the set value (        _(setvalue); c_(setvalue)) is different from the proposed value        (        _(prop.value); c_(prop.value)),    -   and so that distinct set values are determined from distinct        proposed values.

According to a second independent aspect a method for setting parametersin an apparatus for extracorporeal blood treatment is provided, theapparatus comprising:

-   -   a filtration unit (2) having a primary chamber (3) and a        secondary chamber (4) separated by a semi-permeable membrane        (5);    -   a blood withdrawal line (6) connected to an inlet of the primary        chamber (3),    -   a blood return line (7) connected to an outlet of the primary        chamber (3), said blood lines being configured for connection to        a patient cardiovascular system;    -   a dialysis supply line (8) connected to an inlet of the        secondary chamber (4);    -   a dialysis effluent line (13) connected to an outlet of the        secondary chamber (4);    -   a preparation device (9) for preparing a dialysis fluid        connected to said supply line (2) and comprising regulating        means (10) for regulating the composition of the dialysis fluid,    -   a control unit (12) connected to the regulating means (10) and        programmed for obtaining a proposed value (        _(prop.value); c_(prop.value)) of a first parameter for the        dialysis fluid in the dialysis supply line (8), the first        parameter being chosen in the group including a conductivity for        the dialysis fluid, a conductivity-related parameter for the        dialysis fluid, a concentration of at least a substance for the        dialysis fluid, a concentration-related parameter of at least a        substance for the dialysis fluid, the method comprising the        following steps performed by the control unit:        -   obtaining said proposed value (            _(prop.value); c_(prop.value)) of the first parameter for            the dialysis fluid in the dialysis supply line (8);        -   determining a set value (            _(setvalue); c_(setvalue)) for the first parameter as a            function of the proposed value (            _(prop.value); c_(prop.value)) for the first parameter;        -   for at least an interval of proposed values for the first            parameter, determining the set value so that the set value (            _(setvalue); c_(setvalue)) is different from the proposed            value (            _(prop.value); c_(prop.value)), and so that distinct set            values are determined from distinct proposed values.

In a 3^(rd) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter as a linear functionof the proposed value (

_(prop.value); c_(prop.value)) for the first parameter.

In a 4^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter as a function of theproposed value (

_(prop.value); c_(prop.value)) for the first parameter and of apredetermined value (

_(pivot); c_(pivot)) for the first parameter.

In a 5^(th) aspect according to the previous aspect, the control unit(12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter as a function of thedifference between the proposed value (

_(prop.value); c_(prop.value)) for the first parameter and thepredetermined value for the first parameter (

_(pivot); c_(pivot)).

In a 6^(th) aspect according to the previous aspect, the control unit(12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter as a function of aweighted difference between the proposed value (

_(prop.value); c_(prop.value)) for the first parameter and thepredetermined value for the first parameter (

_(pivot); c_(pivot)).

In a 7^(th) aspect according to the previous aspect, the control unit(12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter as a function of theweighted difference between the proposed value (

_(prop.value); c_(prop.value)) for the first parameter and thepredetermined value for the first parameter (

_(pivot); c_(pivot)).

c _(setvalue) =f[β·(c _(prop.value) −c _(pivot))]

_(setvalue) =f[β·(

_(prop.value)−

_(pivot))]

wherein β is a constant chosen in the range 0 to 1: 0<β<1.

In a 8^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter as a linear functionof the proposed value for the first parameter, and to determine the setvalue (

_(setvalue); c_(setvaiue)) for the first parameter as a function of adifference between the proposed value (

_(prop.value); c_(prop.value)) for the first parameter and apredetermined value for the first parameter (

_(pivot); c_(pivot)).

In a 9^(th) aspect according to the previous aspect, the control unit(12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter as a function of theweighted difference between the proposed value (

_(prop.value); c_(prop.value)) for the first parameter and thepredetermined value for the first parameter (

_(pivot); c_(pivot)) according to the following mathematicalrelationship:

c _(setvalue)=β·(c _(prop.value) −c _(pivot))+c _(pivot)

or

_(setvalue)=β·(

_(prop.value)−

_(pivot))+

_(pivot)

in particular, wherein β is a constant chosen in the range 0 to 1:0<β<1, even more in particular included in the range between 0.3 to 0.8:0.3≤β≤0.8.

In a 10^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter as a function of theproposed value (

_(prop.value); c_(prop.value)) for the first parameter and of apredetermined value (

_(pivot); c_(pivot)) for the first parameter, said predetermined value (

_(pivot); c_(pivot)) for the first parameter being chosen in the groupincluding:

-   -   an average pre-dialysis plasma conductivity for the patient or        for a patient population;    -   an average pre-dialysis plasma sodium concentration for the        patient or for a patient population.

In a 11^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured to determine the set value(c_(setvalue)) for the first parameter as a function of the proposedvalue (c_(prop.value)) for the first parameter and of a predeterminedvalue (c_(pivot)) for the first parameter, said predetermined value(c_(pivot)) for the first parameter being a constant value comprisedbetween 130 mmol/l and 143 mmol/l, in particular comprised between 134mmol/l and 140 mmol/l.

In a 12^(th) aspect according to anyone of the previous aspects, for atleast a predetermined value (

_(pivot); c_(pivot)) for the first parameter, the control unit (12) isconfigured to determine the set value (

_(setvalue); c_(setvalue)) so that the set value (

_(setvalue); c_(setvalue)) is equal to the proposed value (

_(prop.value); c_(prop.value)).

In a 13^(th) aspect according to anyone of the previous aspects, in casethe set value (

_(setvalue); c_(setvalue)) for the first parameter determined by thecontrol unit (12) is lower than a lower limit for the first parameter,the set value (

_(setvalue); c_(setvalue)) is set to the lower limit.

In a 14^(th) aspect according to anyone of the previous aspects, in casethe set value (

_(setvalue); c_(setvalue)) for the first parameter determined by thecontrol unit (12) exceeds an upper limit for the first parameter, theset value (

_(setvalue); c_(setvalue)) is set to the upper limit.

In a 15^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter as a linear functionof the proposed value for the first parameter in an interval including apredetermined value (

_(pivot); c_(pivot)) for the first parameter, the control unit beingfurther configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter as a non-linearfunction of the proposed value for the first parameter outside saidinterval.

In a 16^(th) aspect according to anyone of the previous aspects, for atleast said interval of proposed values for the first parameter, thecontrol unit (12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter so that the set value(

_(setvalue); c_(setvalue)) differs from the proposed value (

_(prop.value); c_(prop.value)) by a delta, said delta increasing as theproposed value (

_(prop.value); c_(prop.value)) moves away from a predetermined value (

_(pivot); c_(pivot)) for the first parameter.

In a 17^(th) aspect according to the previous aspect, said deltaincreases linearly in magnitude as the proposed value (

_(prop.value); c_(prop.value)) moves away from a predetermined value (

_(pivot); c_(pivot)) for the first parameter.

In a 18^(th) aspect according to anyone of the previous aspects, outsidesaid interval of proposed values for the first parameter, the controlunit (12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter so that the set value(

_(setvalue); c_(setvalue)) is the same for each proposed value (

_(prop.value); c_(prop.value)).

In a 19^(th) aspect according to anyone of the previous aspects, outsidesaid interval of proposed values for the first parameter, the controlunit (12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter so that the set value(

_(setvalue); c_(setvalue)) differs from the proposed value (

_(prop.value); c_(prop.value)) by a delta, said delta increasing nonlinearly as the proposed value (

_(prop.value); c_(prop.value)) moves away from a predetermined value (

_(pivot); c_(pivot)) for the first parameter.

In a 20^(th) aspect according to anyone of the previous aspects, for atleast said interval of proposed values for the first parameter, thecontrol unit (12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter so that the set value(

_(setvalue); c_(setvalue)) differs from the proposed value (

_(prop.value); c_(prop.value)) by a delta, said delta depending on adistance of the proposed value (

_(prop.value); c_(prop.value)) from a predetermined value (

_(pivot); c_(pivot)) for the first parameter.

In a 21^(st) aspect according to anyone of the previous aspects 16, 17,19 and 20, said delta is positive if the proposed value (

_(prop.value); c_(prop.value)) is lower than a predetermined value (

_(pivot); c_(pivot)) for the first parameter.

In a 22^(nd) aspect according to anyone of the previous aspects 16, 17,19, 20 and 21, said delta is negative if the proposed value (

_(prop.value); c_(prop.value)) is higher than a predetermined value (

_(pivot); c_(pivot)) for the first parameter.

In a 23^(rd) aspect according to anyone of the previous aspects, for atleast said interval of proposed values for the first parameter, thecontrol unit (12) is configured to determine the set value (

_(setvalue); c_(setvalue)) for the first parameter so that:

-   -   the set value (        _(setvalue); c_(setvalue)) is lower than the proposed value (        _(prop.value); c_(prop.value)) if the proposed value (        _(prop.value); c_(prop.value)) is higher than a predetermined        value (        _(pivot); c_(pivot)) for the first parameter; and/or    -   the set value (        _(setvalue); c_(setvalue)) is higher than the proposed value (        _(prop.value); c_(prop.value)) if the proposed value (        _(prop.value); c_(prop.value)) is lower than the predetermined        value (        _(pivot); c_(pivot)) for the first parameter.

In a 24^(th) aspect according to anyone of the previous aspects, thefirst parameter is the concentration of at least a substance in thedialysis fluid, said substance being in particular sodium.

In a 25^(th) aspect according to anyone of the previous aspects, thecontrol unit drives the regulating means (10) for regulating theconductivity or the concentration of at least a substance in thedialysis fluid, the control unit setting the first parameter value forthe dialysis fluid in the dialysis supply line (8) at the calculated setvalue of the first parameter.

In a 26^(th) aspect according to anyone of the previous aspects, thefirst parameter is the concentration of at least a substance in thedialysis fluid, the proposed value for the first parameter being thesubstance concentration set point for running an isotonic dialysis orisonatremic dialysis or an isonatrikalemic dialysis.

In a 27^(th) aspect according to anyone of the previous aspects, thefirst parameter is the concentration of at least a substance in thedialysis fluid, the proposed value for the first parameter being thesubstance concentration set point for running an isoconductive dialysis.

In a 28^(th) aspect according to anyone of the previous aspects, thefirst parameter is the concentration of at least a substance in thedialysis fluid, the proposed value for the first parameter beingfunction of or equal to a plasma sodium concentration value.

In a 29^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured for either calculating the proposedvalue for the first parameter or receiving the proposed value as aninput.

In a 30^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured for calculating the proposed value forthe first parameter as a function of a main contribution term based on aplasma conductivity, a plasma conductivity-related parameter, aconcentration of at least a substance in the blood, aconcentration-related parameter of at least a substance in the blood andas a function of an adjustment contribution term based on aconcentration of at least a substance in the dialysis fluid chosen inthe group including bicarbonate, potassium, acetate, lactate, citrate,magnesium, calcium, sulphate and phosphate.

In a 31^(st) aspect according to the previous aspect, the control unitis configured to calculate the adjustment contribution term based on theconcentration of two or more substances in the dialysis fluid chosen inthe group including bicarbonate, potassium, acetate, lactate, citrate,magnesium, calcium, sulphate and phosphate, in particular as a functionof the concentration of at least three of said substances, optionally asa function of the concentration of bicarbonate, potassium, acetate, andcitrate in the dialysis fluid.

In a 32^(nd) aspect according to anyone of the previous aspects 30 and31, the control unit is configured to calculate the adjustmentcontribution term as a function of the weighted difference inconcentration of at least a substance in the dialysis fluid and the samesubstance in the plasma, said substance being chosen in the groupincluding bicarbonate, potassium, acetate, lactate and citrate, inparticular as a function of the weighted difference in concentration ofat least two of said substances, optionally as a function of thedifference in concentration of bicarbonate, potassium, acetate, andcitrate in the dialysis fluid and plasma.

In a 33^(rd) aspect according to anyone of the previous aspects 30 to32, the main contribution term is based on the plasma conductivity, orthe concentration of at least a substance in the blood, and wherein thefirst parameter of the dialysis fluid is the conductivity of thedialysis fluid, or the concentration of at least a substance in thedialysis fluid, said substance being in particular sodium.

In a 34^(th) aspect according to anyone of the previous aspects 30 to33, the main contribution term is dimensionally a concentration of asubstance in a fluid, particularly wherein the main contribution term isa dialysis fluid concentration of sodium at an isoconductive dialysis.

In a 35^(th) aspect according to anyone of the previous aspects 30 to34, the adjustment contribution term is the sodium concentration setpoint adjustment relative to the sodium concentration set point for theisoconductive dialysis, the adjustment contribution applied to thesodium concentration set point for the isoconductive dialysis provides atreatment chosen in the group including isotonic dialysis, isonatremicdialysis and isonatrikalemic dialysis.

In a 36^(th) aspect according to anyone of the previous aspects 30 to35, the adjustment contribution term is the sodium concentration setpoint adjustment relative to the sodium concentration set point for theisoconductive dialysis, the adjustment contribution applied to thesodium concentration set point for the isoconductive dialysis provides atreatment that removes from, or adds to, the plasma a defined amount ofat least a substance.

In a 37^(th) aspect according to anyone of the previous aspects 30 to36, the control unit is configured to calculate the adjustmentcontribution term as a function of the molar conductivities of at leasta substance in the dialysis fluid chosen in the group including sodiumbicarbonate (NaHCO₃), sodium chloride (NaCl), sodium acetate (NaCH₃COO),potassium chloride (KCl), sodium lactate (NaC₃H₅O₃), and trisodiumcitrate (Na₃C₆H₅O₇), in particular as a function of the molarconductivities of at least two of said substances, in more detail as afunction of the molar conductivities of at least three of saidsubstances, optionally as a function of the molar conductivities ofsodium bicarbonate (NaHCO₃), sodium chloride (NaCl), sodium acetate(NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇) and potassium chloride (KCl).

In a 38^(th) aspect according to anyone of the previous aspects 30 to37, the control unit is configured to calculate the adjustmentcontribution term as a function of a difference between a first molarconductivity of a substance chosen in the group including sodiumbicarbonate (NaHCO₃), sodium acetate (NaCH₃COO), trisodium citrate(Na₃C₆H₅O₇), sodium lactate (NaC₃H₅O₃), potassium chloride (KCl), and amolar conductivity of sodium chloride (NaCl).

In a 39^(th) aspect according to anyone of the previous aspects 30 to38, the control unit is configured to calculate the adjustmentcontribution term as a function of an estimated or measured plasma waterconcentration of at least a substance chosen in the group includingbicarbonate, potassium, acetate, lactate and citrate, in particular as afunction of the estimated or measured plasma water concentration of atleast two of said substances, in more detail as a function of theestimated plasma water concentration of at least three of saidsubstances, optionally as a function of the estimated plasma waterconcentration of bicarbonate, potassium and acetate.

In a 40^(th) aspect according to anyone of the previous aspects 30 to39, the control unit is configured to calculate the adjustmentcontribution term as an algebraic sum of at least two components, afirst component being function of the difference in concentration of atleast a substance in the dialysis fluid and the same substance in theblood plasma, the second component being function of the weighteddifference in concentration of at least a second substance in thedialysis fluid and the same second substance in the blood plasma,particularly wherein said substance is chosen in the group includingbicarbonate anions (HCO₃), acetate anions (CH₃COO⁻), citrate anions(C₆H₅O₇ ³), and potassium ions (K⁺).

In a 41^(st) aspect according to anyone of the previous aspects 30 to40, the control unit is configured to calculate the adjustmentcontribution term as an algebraic sum of at least two components, afirst component being function of a concentration of at least asubstance in the dialysis fluid and/or in the blood plasma, a secondcomponent being function of a concentration of at least a secondsubstance in the dialysis fluid and/or in the blood plasma, particularlywherein said substance is chosen in the group including bicarbonateanions (HCO₃), acetate anions (CH₃COO⁻), citrate anions (C₆H₅O₇ ³⁻), andpotassium ions (K⁺).

In a 42^(nd) aspect according to anyone of the previous aspects 30 to41, the control unit is configured to calculate the adjustmentcontribution term as a function of at least a ratio between one flowrate, in particular the dialysate flow rate at the outlet of thesecondary chamber (4), and an efficiency parameter of the filtrationunit (2), in particular a clearance of the filtration unit (2),optionally the urea clearance.

In a 43^(rd) aspect according to anyone of the previous aspects, thecontrol unit is further configured to obtain a plasma conductivity andin particular to calculate a plasma conductivity as a function of thedialysate flow rate at the outlet of the secondary chamber (4) and theblood flow rate in the blood lines (6, 7), the proposed value (

_(prop.value); c_(prop.value)) for the first parameter being function ofthe plasma conductivity.

In a 44^(th) aspect according to anyone of the previous aspects, thecontrol unit is further configured to obtain a plasma conductivity andin particular to calculate a plasma conductivity as a function of atleast an efficiency parameter of the filtration unit (2), in particulara clearance of the filtration unit (2), optionally the urea clearance,the proposed value (

_(prop.value); c_(prop.value)) for the first parameter being function ofthe plasma conductivity.

In a 45^(th) aspect according to anyone of the previous aspects, thecontrol unit is further configured to obtain a plasma conductivity andin particular to calculate a plasma conductivity as a function of atleast an initial conductivity of the dialysate and of at least aconductivity of the dialysis fluid in the dialysis supply line (8), theproposed value (

_(prop.value); c_(prop.value)) for the first parameter being function ofthe plasma conductivity.

In a 46^(th) aspect according to anyone of the previous aspects, thecontrol unit is programmed to allow selection of at least one treatmentmode chosen in the group including isotonic dialysis, isonatremicdialysis and isonatrikalemic dialysis, the control unit is configured todrive the regulating means as a function of the calculated set value (

_(setvalue); c_(setvalue)) and of the chosen treatment mode to seteither a desired dialysis fluid inlet conductivity or a desired dialysisfluid inlet substance concentration, in particular said substance beingsodium.

In a 47^(th) aspect according to anyone of the previous aspects, thefirst parameter is the dialysis fluid conductivity.

In a 48^(th) aspect according to anyone of the previous aspects, thefirst parameter is the dialysis fluid conductivity, the proposed value (

_(prop.value)) for the first parameter being the conductivity set pointfor running an isotonic dialysis or isonatremic dialysis or anisonatrikalemic dialysis or an isoconductive dialysis.

In a 49^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is further programmed for calculating a valuerepresentative of the parameter of the blood in said blood lines, theblood parameter being chosen in the group including a plasmaconductivity, a plasma conductivity-related parameter, a concentrationof at least a substance in the blood, a concentration-related parameterof at least a substance in the blood.

In a 50^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is further programmed for receiving as an input avalue representative of the parameter of the blood in said blood lines,the blood parameter being chosen in the group including a plasmaconductivity, a plasma conductivity-related parameter, a concentrationof at least a substance in the blood, a concentration-related parameterof at least a substance in the blood.

In a 51^(st) aspect according to anyone of the previous aspects, thecontrol unit (12) is programmed for storing in a memory a valuerepresentative of the parameter of the blood in said blood lines, saidvalue representative of the parameter of the blood being not calculatedby the control unit, the blood parameter being chosen in the groupincluding a plasma conductivity, a plasma conductivity-relatedparameter, a concentration of at least a substance in the blood, aconcentration-related parameter of at least a substance in the blood.

In a 52^(nd) aspect according to anyone of the previous aspects 30 to42, the adjustment contribution term has a negative value.

In a 53^(rd) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate a plasma conductivity as afunction of at least one flow rate, in particular said flow rate beingchosen in the group including the dialysate flow rate at the outlet ofthe secondary chamber (4) and the blood flow rate in the blood lines (6,7).

In a 54^(th) aspect according to the previous aspect, the control unitis configured to calculate a plasma conductivity as a function of thedialysate flow rate at the outlet of the secondary chamber (4) and theblood flow rate in the blood lines (6, 7).

In a 55^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate a plasma conductivity as afunction of at least an efficiency parameter of the filtration unit (2),in particular a clearance of the filtration unit (2), optionally theurea clearance.

In a 56^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate a plasma conductivity as afunction of at least an initial conductivity of the dialysate.

In a 57^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate a plasma conductivity as afunction of at least a conductivity of the dialysis fluid in thedialysis supply line (8).

In a 58^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate a plasma conductivity accordingto the following formula (IV):

$\kappa_{p,1}^{\prime} = {\kappa_{0,{do}} + {\frac{Q_{do}}{Q_{Bset}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}$

wherein:

 _(p, 1) Plasma conductivity first estimate; Q_(do) Dialysate flow rateat the filtration unit outlet; Q_(bset) Set blood flow rate or bloodwater flow rate at the filtration unit inlet;

 _(0, di) Dialysis fluid conductivity at the filtration unit inlet for apure electrolyte solution;

 _(0, do) Dialysate conductivity at the filtration unit outlet for apure electrolyte solution;

In a 59^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate a plasma conductivity accordingto the following formula (V):

$\kappa_{p,1}^{''} = {\kappa_{0,{di}} + {\frac{Q_{do}}{K_{u}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}$

wherein:

 _(p, 1) Plasma conductivity first estimate; Q_(do) Dialysate flow rateat the filtration unit outlet; K_(u) Filtration unit clearance for urea;

 _(0, di) Dialysis fluid conductivity at the filtration unit inlet for apure electrolyte solution;

 _(0, do) Dialysate conductivity at the filtration unit outlet for apure electrolyte solution;

In a 60^(th) aspect according to anyone of the previous aspects,immediately after calculating an initial plasma conductivity, thecontrol unit is configured to drive the regulating means (10) to changethe composition of the dialysis fluid and to set the dialysis fluidconductivity substantially equal to the calculated plasma conductivity.

In a 61^(st) aspect according to the previous aspect, after setting thedialysis fluid conductivity substantially equal to the calculated plasmaconductivity, the control unit is configured to execute a secondcalculating step, based on a second determined initial conductivity ofthe dialysate and on a second corresponding conductivity of the dialysisfluid in the dialysis supply line (8), of a second estimate of theinitial plasma conductivity, said calculating the second estimate beingperformed maintaining the dialysis fluid conductivity substantiallyconstant and substantially equal to the calculated plasma conductivity.

In a 62^(nd) aspect according to anyone of the previous aspects, aftercalculating the second estimate of the initial plasma conductivity, thecontrol unit is configured to drive the regulating means (10) to changethe composition of the dialysis fluid and to set the dialysis fluidconductivity substantially equal to said second estimate.

In a 63^(rd) aspect according to anyone of the previous aspects, thecontrol unit is programmed to allow selection of at least one treatmentmode chosen in the group including isotonic dialysis, isonatremicdialysis and isonatrikalemic dialysis, the control unit is configured todrive the regulating means as a function of the calculated plasmaconductivity and of the chosen treatment mode to set either a desireddialysis fluid inlet conductivity or a desired dialysis fluid inletsubstance concentration, in particular said substance being sodium.

In a 64^(th) aspect according to the previous aspect, the control unitis programmed to keep the desired dialysis fluid inlet conductivitysubstantially constant throughout the remainder of the treatment.

Further characteristics and advantages of the present invention willbetter emerge from the detailed description that follows of at least anembodiment of the invention, illustrated by way of non-limiting examplein the accompanying figures of the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The description will now follow, with reference to the appended figures,provided by way of non-limiting example, in which:

FIG. 1 schematically represents an extracorporeal blood treatmentapparatus made according to an illustrating embodiment;

FIGS. 2 to 7 are diagrams showing on the X-axis the proposed value forthe sodium concentration in the dialysis fluid and on the Y-axis the setvalue; functions, according to some embodiments of the invention,designed to convert the proposed value to the set value for the sodiumconcentration are illustrated; and

FIG. 6a is an enlarged view of the correspondingly encircled area ofFIG. 6.

DETAILED DESCRIPTION

FIG. 1 illustrates an extracorporeal blood treatment apparatus 1 in anembodiment of the invention.

An example of a hydraulic circuit 100 is schematically illustrated, butit is to be noted that the specific structure of the hydraulic circuit100 is not relevant for the purposes of the present invention andtherefore other and different circuits to those specifically shown inFIG. 1 might be used in consequence of the functional and design needsof each single medical apparatus.

The hydraulic circuit 100 exhibits a dialysis fluid circuit 32presenting at least one dialysis fluid supply line 8, destined totransport a dialysis fluid from at least one source 14 towards atreatment station 15 where one or more filtration units 2, or dialyzers,operate.

The dialysis fluid circuit 32 further comprises at least one dialysiseffluent line 13, destined for the transport of a dialysate liquid(spent dialysate and liquid ultrafiltered from the blood through asemipermeable membrane 5) from the treatment station 15 towards anevacuation zone, schematically denoted by 16 in FIG. 1.

The hydraulic circuit cooperates with a blood circuit 17, alsoschematically represented in FIG. 1 in its basic component parts. Thespecific structure of the blood circuit is also not fundamental, withreference to the present invention. Thus, with reference to FIG. 1, abrief description of a possible embodiment of a blood circuit is made,which is however provided purely by way of non-limiting example.

The blood circuit 17 of FIG. 1 comprises a blood withdrawal line 6designed to remove blood from a vascular access 18 and a blood returnline 7 designed to return the treated blood to the vascular access 18.

The blood circuit 17 of FIG. 1 further comprises a primary chamber 3, orblood chamber, of the blood filtration unit 2, the secondary chamber 4of which is connected to the hydraulic circuit 100.

In greater detail, the blood withdrawal line 6 is connected at the inletof the primary chamber 3, while the blood return line 7 is connected atthe outlet of the primary chamber 3.

In turn, the dialysis supply line 8 is connected at the inlet of thesecondary chamber 4, while the dialysis effluent line 13 is connected atthe outlet of the secondary chamber 4.

The filtration unit 2, for example a dialyzer or a plasma filter or ahemofilter or a hemodiafilter, comprises, as mentioned, the two chambers3 and 4 which are separated by a semipermeable membrane 5, for exampleof the hollow-fiber type or plate type.

The blood circuit 17 may also comprise one or more air separators 19: inthe example of FIG. 1 a separator 19 is included at the blood returnline 7, upstream of a safety valve 20.

Of course other air separators may be present in the blood circuit, suchas positioned along the blood withdrawal line 6.

The safety valve 20 may be activated to close the blood return line 7when, for example, for security reasons the blood return to the vascularaccess 18 has to be halted.

The extracorporeal blood treatment apparatus 1 may also comprise one ormore blood pumps 21, for example positive displacement pumps such asperistaltic pumps; in the example of FIG. 1, a blood pump 21 is includedon the blood withdrawal line 6.

The apparatus of above-described embodiment may also comprise a userinterface 22 (e.g. a graphic user interface or GUI) and a control unit12, i.e. a programmed/programmable control unit, connected to the userinterface.

The control unit 12 may, for example, comprise one or more digitalmicroprocessor units or one or more analog units or other combinationsof analog units and digital units. Relating by way of example to amicroprocessor unit, once the unit has performed a special program (forexample a program coming from outside or directly integrated on themicroprocessor card), the unit is programmed, defining a plurality offunctional blocks which constitute means each designed to performrespective operations as better described in the following description.

In combination with one or more of the above characteristics, themedical apparatus may also comprise a closing device operating, forexample, in the blood circuit 17 and/or in the dialysis fluid circuit 32and commandable between one first operating condition, in which theclosing device allows a liquid to flow towards the filtration unit 2,and a second operative position, in which the closing device blocks thepassage of liquid towards the filtration unit 2.

In this case, the control unit 12 may be connected to the closing deviceand programmed to drive the closing device to pass from the first to thesecond operative condition, should an alarm condition have beendetected.

In FIG. 1 the closing device includes the safety valve 20 (e.g. asolenoid valve) controlled by the unit 12 as described above. Obviouslya valve of another nature, either an occlusive pump or a further memberconfigured to selectively prevent and enable fluid passage may be used.

Alternatively or additionally to the safety valve 20, the closing devicemay also comprise a bypass line 23 which connects the dialysis fluidsupply line 8 and the dialysis effluent line 13 bypassing the filtrationunit 2, and one or more fluid check members 24 connected to the controlunit 12 for selectively opening and closing the bypass line 23. Thecomponents (bypass line 23 and fluid check members 24), which may bealternative or additional to the presence of the safety valve 20 arerepresented by a broken line in FIG. 1.

The check members 24 on command of the control unit close the fluidpassage towards the treatment zone and connect the source 14 directlywith the dialysis effluent line 13 through the bypass line 23.

Again with the aim of controlling the fluid passage towards thefiltration unit 2, a dialysis fluid pump 25 and a dialysate pump 26 maybe included, located respectively on the dialysis fluid supply line 8and on the dialysis effluent line 13 and also operatively connected tothe control unit 12.

The apparatus also comprises a dialysis fluid preparation device 9 whichmay be of any known type, for example including one or more concentratesources 27, 28 and respective concentrate pumps 29, 30 for the delivery,as well as at least a conductivity sensor 35.

Of course other kinds of dialysis fluid preparation devices 9 might beequivalently used, having a single or further concentrate sources and/ora single or more pumps.

Since the dialysis apparatus may comprise various liquid sources 14 (forexample one or more water sources, one or more concentrate sources 27,28, one or more sources 33 of disinfectant liquids) connected to thedialysis supply line 8 with respective delivery lines 36, 37 and 38, theapparatus may exhibit, at each delivery line, a respective check member(not all are shown) and, for example, comprising a valve member 31 and34 and/or an occlusive pump.

The preparation device 9 may be any known system configured for on-linepreparing dialysis fluid from water and concentrates.

The dialysis supply line 8 fluidly connects the preparation device 9 forpreparing dialysis fluid to the filtration unit 2. The preparationdevice 9 may be, for example, the one described in the U.S. Pat. No.6,123,847 the content of which is herein incorporated by reference.

As shown, the dialysis supply line 8 connects the preparation device 9for preparing dialysis fluid to the filtration unit 2 and comprises amain line 40 whose upstream end is intended to be connected to a source14 of running water.

Delivery line/s 36/37 is/are connected to this main line 40, the freeend of which delivery line/s is/are intended to be in fluidcommunication (for example immersed) in a container/s 27, 28 for aconcentrated saline solution each containing sodium chloride and/orcalcium chloride and/or magnesium chloride and/or potassium chlorideand/or bicarbonate.

Concentrate pump/s 29, 30 is/are arranged in the delivery line/s 36/37in order to allow the metered mixing of water and concentrated solutionin the main line 40. The concentrate pump/s 29, 30 is/are driven on thebasis of the comparison between 1) a target conductivity value for themixture of liquids formed where the main line 40 joins the deliveryline/s 36/37, and 2) the value of the conductivity of this mixturemeasured by means of a conductivity sensor 35 arranged in the main line40 immediately downstream of the junction between the main line 40 andthe delivery line/s 36/37.

Therefore, as mentioned, the dialysis fluid may contain, for example,ions of sodium, calcium, magnesium and potassium and the preparationdevice 9 may be configured to prepare the dialysis fluid on the basis ofa comparison between a target conductivity value and an actualconductivity value of the dialysis fluid measured by the conductivitysensor 35 of the device 9.

The preparation device 9 comprises regulating means 10, of a known type(i.e. concentrate pump/s 29, 30), which is configured to regulate theconcentration of a specific substance, in particular an ionic substance,in the dialysis fluid. Generally it is advantageous to control thesodium concentration of the dialysis fluid.

The dialysis supply line 8 forms an extension of the main line 40 of thepreparation device 9 for preparing dialysis fluid. Arranged in thisdialysis supply line, in the direction in which the liquid circulates,there are the first flow meter 41 and the dialysis fluid pump 25.

The dialysis effluent line 13 may be provided with a dialysate pump 26and a second flow meter 42. The first and second flow meters 41, 42 maybe used to control (in a known manner) the fluid balance of a patientconnected to the blood circuit 17 during a dialysis session.

A sensor 11 is provided on the dialysis effluent line 13, immediatelydownstream the filtration unit 2, to measure a parameter value of thedialysate in the dialysis effluent line 13.

In detail, the parameter of the dialysate, which is measured by thesensor 11 is at least one chosen in the group consisting of conductivityof the dialysate, a conductivity-related parameter of the dialysate,concentration of at least a substance in the dialysate and aconcentration-related parameter of at least a substance in thedialysate.

In detail the sensor 11 is a conductivity sensor, which is connected tothe dialysis effluent line 13, and is configured to detect conductivityvalues of the dialysate downstream of the filtration unit 2.

Alternatively (or in combination) sensor 11 may include a concentrationsensor configured for measuring the concentration of at least onesubstance in the dialysate, such as sodium concentration.

Correspondingly, sensor 35 on the dialysis fluid supply line may be nota conductivity sensor and, differently, may include a concentrationsensor configured for measuring the concentration of at least onesubstance in the dialysis fluid, such as sodium concentration.

The control unit 12 of the dialysis apparatus represented in FIG. 1 maybe connected to a (graphic) user interface 22 through which it mayreceive instructions, for example target values, such as blood flow rateQ_(b), dialysis fluid flow rate Q_(di), infusion liquid flow rateQ_(inf) (where appropriate), patient weight loss WL. The control unit 12furthermore may receive detected values by the sensors of the apparatus,such as the aforementioned flow meters 41, 42, the (e.g. conductivity)sensor 35 of the preparation device 9 and the (e.g. conductivity) sensor11 in the dialysis effluent line 13. On the basis of the instructionsreceived and the operating modes and algorithms which have beenprogrammed, the control unit 12 drives the actuators of the apparatus,such as the blood pump 21, the aforementioned dialysis fluid anddialysate pumps 25, 26, and the preparation device 9.

As already mentioned, the described embodiments are intended to benon-limiting examples. In particular the circuits of FIG. 1 should notbe interpreted as defining or limiting, as an apparatus such as in theinvention may comprise other additional or alternative components tothose described.

For example an ultrafiltration line may be included, with at least onerespective pump connected to the dialysis effluent line 13.

One or more infusion lines 39 may also be included, with respectiveinfusion pumps 43 or flow regulation valves, the infusion lines beingconnected up to the blood return line 7 and/or the blood withdrawal line6 and/or directly to the patient. The liquid sources for the infusionlines may be pre-packaged bags 44 and/or liquids prepared by theapparatus itself.

In the example of FIG. 1, an infusion line 39 is shown directlyconnected to the blood return line 7, in particular to the air separator19. The infusion line 39 may either receive infusion liquid from apre-packaged bag 44 (solid line 45 a) or from an online preparationtrough branch 45 b (dotted line).

Of course a pre-infusion line may be alternatively or additionallyprovided receiving the infusion liquid from a bag or from an onlinepreparation device.

The blood circuit of FIG. 1 is intended for double needle treatments;however, this is a non-limiting example of the blood set.

Indeed, the apparatus may be configured to perform single needletreatments, i.e. the patient is connected to the extracorporeal bloodcircuit by way of a single needle and the extracorporeal line from thepatient is then split into a withdrawal line and a return line, using,for example, a ‘Y’ connector. During single needle treatment, a bloodwithdrawal phase removing blood from patient is alternated to a bloodreturn phase in which blood is restituted to the patient.

Furthermore one or more devices for measuring specific substanceconcentrations might be implemented either (or both) in the dialysisfluid side or (and) in the blood side of the hydraulic circuit.Concentration of calcium, potassium, magnesium, bicarbonate, and/orsodium might be desired to be known.

Finally, the above-cited one or more pumps and all the other necessarytemperature, pressure and concentration sensors may operate either onthe dialysis supply line 8 and/or on the dialysis effluent line 13, inorder to adequately monitor the preparation and movement of the liquidin the hydraulic circuit.

Given the above description of a possible embodiment of extracorporealblood treatment apparatus, thereafter the specific working of theapparatus and the algorithm programming the control unit are described.

Definitions

We define the “dialysis fluid” as the fluid prepared and introduced tothe second chamber (4) of the filtration unit (2), the dialyzer. Thedialysis fluid may also be denoted “fresh dialysis fluid”.

We define the “dialysate” as the fluid from the outlet from the secondchamber (4) of the filtration unit (2), the dialyzer. Dialysate is thespent dialysis fluid, comprising the uremic toxins removed from theblood.

We define ‘isonatremic dialysis’ as a treatment where the sodiumconcentration of the dialysis fluid does not change pre- topost-filtration unit 2.

We define ‘isotonic dialysis’, as a dialysis where the tonicity of thedialysis fluid does not change pre- to post-filtration unit 2.

We define an ‘isonatrikalemic dialysis’, as a treatment where the sum ofsodium and potassium concentrations of the dialysis fluid does notchange pre- to post-filtration unit 2.

We define ‘isoconductive dialysis’, as a dialysis treatment where theconductivity of the dialysis fluid does not change pre- topost-filtration unit 2,

_(di)=

_(do).

We define ‘plasma conductivity’ (PC,

_(p)) as the conductivity of the dialysis fluid in an isoconductivedialysis.

In this application, when “isotonic treatment” word is used alone, thisactually implies isotonic, isonatremic or isonatrikalemic dialyses.

Glossary

The following terms are consistently used throughout the equationsprovided in the following description of the detailed working of theextracorporeal blood treatment apparatus.

Name Description Unit

 _(d, pre) = 

 _(di) Dialysis fluid conductivity upstream the mS/cm filtration unit(corresponding to final conductivity of the dialysis fluid);

 _(d, post) = 

 _(do) Dialysate conductivity downstream the mS/cm filtration unit; PC= 

 _(p) Plasma conductivity; mS/cm Q_(di) Dialysis fluid flow rate atfiltration mL/min unit inlet; Q_(uf) Ultrafiltration flow rate; mL/minQ_(do) Dialysate flow rate at filtration unit mL/min outlet (i.e.,Q_(di) + Q_(uf) ); Q_(bset) Set blood flow rate at filtration unitmL/min inlet; Q_(b) Real blood flow rate at filtration unit mL/min inlet(set blood flow compensated for arterial pressure); Q_(bw) Real bloodwater flow rate at filtration mL/min unit inlet; K_(u) Filtration unitclearance for urea; mL/min KoA Urea mass transfer area coefficient ofmL/min filtration unit (average of normally used dialyzers);C_(di, Na, start) Dialysis fluid concentration of sodium mmol/L ions(Na⁺) at the start of treatment, automatically calculated and set by themachine before the start of the treatment; C_(di, Na, )

 p, pre Dialysis fluid concentration of sodium mmol/L ions (Na⁺) atisoconductive dialysis, i.e., when the dialysis fluid conductivity 

 _(di) matches the estimated pre-dialysis plasma conductivity 

 _(p, pre); C_(di, Na, set, isotonic) Dialysis fluid concentration ofsodium mmol/L ions (Na⁺)to provide isotonic dialysis;C_(di, Na, isotonic, adj) Sodium set point adjustment (relative tommol/L isoconductive state) required to provide isotonic dialysis;C_(di, Na, set, isoNa) Dialysis fluid concentration of sodium mmol/L toprovide isonatremic dialysis; C_(di, Na, isoNa, adj) Sodium set pointadjustment (relative to mmol/L isoconductive state) required to provideisonatremic dialysis; C_(di, Na, set, isoNa+K) Dialysis fluidconcentration of sodium mmol/L to provide isonatrikalemic dialysis;C_(di, Na, isoNa+K, adj) Sodium set point adjustment (relative to mmol/Lisoconductive state) required to provide isonatrikalemic dialysis;C_(di, HCO3) Dialysis fluid concentration of mmol/L bicarbonate as setby the operator; C_(di, K) Dialysis fluid concentration of mmol/Lpotassium ions (K⁺) as determined by the used concentrate; C_(di, Ac)Dialysis fluid concentration of acetate mmol/L as determined by the usedconcentrate; C_(di, g) Dialysis fluid concentration of glucose mmol/L asdetermined by the used concentrate; C_(pw, Na) Estimated or measuredpre-dialysis mmol/L concentration of sodium ions (Na⁺) in plasma waterC_(pw, HCO3) Estimated or measured pre-dialysis mmol/L concentration ofbicarbonate anions (HCO₃ ⁻) in plasma water C_(pw, Ac) Estimated ormeasured pre-dialysis mmol/L concentration of acetate anions (CH3COO⁻)in plasma water C_(pw, K) Estimated or measured pre-dialysis mmol/Lconcentration of potassium ions (K⁺) in plasma water C_(p, g) Estimatedor measured pre-dialysis mmol/L concentration of glucose in plasmaC_(p, u) Estimated or measured pre-dialysis mmol/L concentration of ureain plasma f_(bw) Apparent blood water fraction, i.e., the Dimensionlesspart of whole blood that appears as pure water for urea; f_(pw) Plasmawater fraction, i.e., the part of Dimensionless plasma that is purewater; f_(g, KB) Glucose clearance fraction, i.e., the Dimensionlessrelative glucose clearance compared to urea clearance;

 _(0, di) Dialysis fluid conductivity at mS/cm filtration unit inlet fora pure electrolyte solution (i.e. without glucose, either because theactual solution does not contain glucose, or because the conductivityhas been compensated for the influence of glucose) ;

 _(0, do) Dialysate conductivity at filtration mS/cm unit outlet for apure electrolyte solution (i.e. without glucose and urea, because theconductivity has been compensated for the influence of glucose andurea);

 _(p, 1 and) 

 _(p, 2) 1st and 2nd estimate of plasma mS/cm conductivity;

 _(p, pre) Estimate of plasma conductivity at mS/cm beginning oftreatment (representing a pre-dialysis value);

 _(isotonic) Conductivity offset between 

 _(do) and 

 _(di) to mS/cm provide isotonic dialysis (correspondent toC_(di, Na, isotonic, adj));

 _(isoNa) Conductivity offset between 

 _(do) and 

 _(di) to mS/cm provide isonatremic dialysis (correspondent toc_(di, Na, isoNa, adj));

 _(isoNa+K) Conductivity offset between 

 _(do) and 

 _(di) to mS/cm provide isonatrikalemic dialysis (correspondent toc_(di, Na, isoNa+K, adj));

 _(rest1) Conductivity contribution from lesser mS/cm solutes 1;

 _(rest2) Conductivity contribution from lesser mS/cm solutes 2;

 _(rest3) Conductivity contribution from lesser mS/cm solutes 3; γ_(g)Conductivity correction term for M−1 = L/mol glucose; γ_(u) Conductivitycorrection term for urea; M−1 = L/mol

Molar conductivity of sodium bicarbonate L · mS/mol · cm (NaHCO₃) ationic strength 150 mM; M 

  _(NaCl) Molar conductivity of sodium chloride L · mS/mol · cm (NaCl)at ionic strength 150 mM; M 

  _(NaAc) Molar conductivity of sodium acetate L · mS/mol · cm(NaCH₃COO) at ionic strength 150 mM; M 

  _(KCl) Molar conductivity of potassium chloride L · mS/mol · cm (KCl)at ionic strength 150 mM; T Set total treatment time; min t Elapsed timeinto treatment; Min α Donnan factor; Dimensionless

 _(prop. value) Proposed value for conductivity in the mS/cm dialysisfluid;

 _(setvalue) Set value for conductivity in the mS/cm dialysis fluid;

 _(pivot) Predetermined value for conductivity mS/cm around whichequation pivots; C_(prop. value) Proposed value for a substance mmol/Lconcentration in the dialysis fluid; C_(setvalue) Set value for asubstance concentration mmol/L in the dialysis fluid; C_(pivot)Predetermined value for a substance mmol/L concentration around whichequation pivots; C_(Na, prop. value) Proposed value for sodiumconcentration mmol/L in the dialysis fluid; C_(Na), _(setvalue) Setvalue for sodium concentration in mmol/L the dialysis fluid; C_(Na),_(pivot) Predetermined value for sodium mmol/L concentration aroundwhich equation pivots; β Slope of the linear equation betweenDimensionless proposed value and set value for conductivity or asubstance concentration in the dialysis fluid;

The Donnan factor indicates a value of electroneutrality to be kept overthe membrane. For estimating the Donnan factor reference is made toTrans Am Soc Artif Intern Organs, 1983; 29; 684-7, “Sodium Fluxes duringhemodialysis”, Lauer A., Belledonne M., Saccaggi A., Glabman S., BoschJ.

Solution Proposal

The technical solution here described consists of three main parts:

-   -   Estimating PC at the beginning of the treatment (i.e.,        _(p,pre));    -   Determining the dialysis fluid sodium concentration such that,        if applied, the dialysis fluid tonicity (or sodium or        sodium+potassium) is substantially not changed during its        passage through the filtration unit;    -   Setting dialysis fluid sodium concentration applying an        additional offset according to a specific function particularly        to take into account of high deviations from an average        pre-dialysis plasma sodium concentration;    -   Maintaining the dialysis fluid composition throughout the whole        treatment.

The various steps of the proposed method described below are intended tobe performed by the control unit 12 of the extracorporeal bloodtreatment device 1, even if not explicitly stated.

In particular a treatment session is started, preferably, but notnecessarily, as a double needle hemodialysis treatment.

The user shall input the prescription values through the user interface22. For example the set values for total weight loss WL and totaltreatment time T are provided, as well as the blood flow rate Q_(b) andthe fresh dialysis flow rate a_(di).

Other parameters may be entered through the user interface, such as bagtype, sodium user limits, etc.

The operator has to further input the ‘bicarbonate’ set before startingthe treatment.

The control unit 12 calculates either the initial dialysis fluidconductivity or the initial concentration of at least one solute, e.g.sodium, in the dialysis fluid in order to start with a dialysis fluidconductivity as close as possible to the expected patient pre-dialyticplasma conductivity.

In order to not disturb the tonicity of the patient, it is necessary toset the fluid composition as quickly as possible so that the patientinitial plasma conductivity is not inadvertently changed. Thus,estimating of the plasma conductivity has to be done as rapidly aspossible when treatment starts; moreover, since the estimation ispreferably performed only once, this measure should be as reliable aspossible.

In this respect it is worth to note that, in the following detaileddescription, reference is made to regulating means controllingconcentration of an ionic substance, in detail sodium concentration, inthe preparation of the dialysis fluid so as to obtain a desiredconductivity of the dialysis fluid.

However, regulating means directly regulating the overall dialysis fluidconductivity is also included in the spirit of the present descriptionor, alternatively, regulating means modifying the concentration of adifferent ionic substance is included in the present description, too.

Given the above, the control unit 12 sets a first parameter value forthe dialysis fluid in the dialysis fluid supply line 8 at an initial setpoint; in general the first parameter of the dialysis fluid is eitherthe conductivity of the dialysis fluid, or a conductivity-relatedparameter of the dialysis fluid, or concentration of at least asubstance (in particular an ionic substance and in more detail sodium)in the dialysis fluid, or a concentration-related parameter of at leasta substance (e.g. sodium) in the dialysis fluid.

In detail, the control unit 12 is configured to set the first parametervalue for the dialysis fluid at the initial set point so that a dialysisfluid conductivity matches a first estimate of the plasma conductivityof the blood.

In the specific, the control unit 12 calculates the initial set point ofthe substance concentration and drives the regulating means 10 acting onthe sodium concentration in the dialysis fluid.

The set point is calculated before starting the blood circulation (i.e.before starting the treatment).

In order to calculate the dialysis composition initial set pointalternative ways might be used, e.g. determine a certain sodiumconcentration (see below), or using an average plasma conductivity froma large population, or using an average plasma conductivity from a largepopulation corrected for the composition of the dialysis fluid, orcalculate based on historic patient data.

In any case, the initial set point for the dialysis fluid is calculatedby the control unit 12 so that the expected plasma conductivity is thebest guess of plasma conductivity that may be calculated, without priorknowledge of the individual patient.

In general terms, the control unit is configured to calculate theinitial set point of the substance concentration to be set (e.g. sodium)in the dialysis fluid as a function of the difference in concentrationof at least one (and in detail several) further substance in thedialysis fluid and the same further substance in the plasma.

Specifically, the control unit 12 is configured to calculate the initialset point of sodium concentration to be set in the dialysis fluid beforethe start of the treatment using the following relationship:

$\begin{matrix}{c_{{di},{Na},{start}} = {{\alpha*c_{{pw},{Na}}} + {\frac{1}{M_{\kappa_{NaCl}}}\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)++}\frac{1}{M_{\kappa_{NaCl}}}\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)} + {\frac{M_{\kappa_{KCl}}}{M_{\kappa_{NaCl}}}{\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)++}\frac{1}{M_{\kappa_{NaCl}}}\frac{Q_{do}}{K_{u}}\kappa_{{rest}\; 3}}}} & (1)\end{matrix}$

wherein the used symbols meaning is clarified in the glossary section.

Since K_(u) may not be known at dialysis start, a fixed value equal toQ_(di)/2 may be possibly used or calculated by a formula taking thefiltration unit characteristics as mean value for the used type offiltration unit or the value for the actual filtration unit.

Of course, different mathematical relationships may be used taking intoaccount exclusively some of the considered substances and/or exclusivelysome of the conductivities and/or molar differences.

Once the sodium initial set point has been calculated and acorresponding dialysis fluid has been prepared by the control unit 12driving the regulating means 10, the treatment may start.

The dialysis fluid is circulated through the dialysis fluid circuit 32and the secondary chamber 4 of the filtration unit 2 so as to exchangewith blood.

Correspondingly, blood is withdrawn from the patient and circulated inthe extracorporeal blood circuit 17 and particularly is circulatedthrough the primary chamber 3 of the filtration unit 2.

At least one, and in general a plurality, of consecutive initial valuesof the parameter (in the specific example, the conductivity) of thedialysate downstream of the secondary chamber 4 are measured at thebeginning of the treatment through sensor 11.

The control unit 12 is configured to validate and further process themeasurement of an initial value of the conductivity of the dialysate assoon as the diffusion process in the filtration unit 2 reaches stableconditions.

Indeed, a transient exists when dialysis fluid and blood startexchanging during which the dialyzer outlet conductivity is not stable;during the transient period the measured outlet conductivity valuesshould be disregarded.

The stability condition may be determined by observing, on a 1-minutewindow, the first derivative of

_(do) and checking when it is lower in size than a fixed threshold. Oncethis stability criterion is fulfilled,

_(do) is taken as the median value on the 1-minute window. The firstderivative is used to avoid the presence of possible drifts in theoutlet conductivity. Extracting the median and/or the average value of

_(do) allows discharging possible outliers of the outlet conductivitysignal from the average calculation.

In order to minimize the time needed to reach stability conditions,changes in dialysis fluid flow rate and in bicarbonate prescription maybe prevented during this preliminary isotonic sodium identificationphase.

The control unit 12 may compensate the measured initial conductivityvalue of the dialysate as a function of the concentration of glucoseand/or urea. Alternatively, account of glucose and urea may be takenonce the plasma conductivity is determined and an adjustment factorcalculated as explained in the following description.

Correction based on main electrically neutral substances is optional andmay be used or not to increase accuracy.

It is worth to note that the initial conductivity of the fresh dialysisfluid upstream the secondary chamber 4 may be either measured or takenas the set value for dialysis conductivity.

In general, it is preferred to measure the initial conductivity of thedialysis fluid through the sensor 35, too.

It is important to underline that the initial setting of the sodiumconcentration calculated or determined as above stated to be as close aspossible to the expected plasma conductivity (eq. 1) may be optional,meaning that the method for estimating the initial plasma conductivitymay be performed even if the sodium content of the dialysis conductivityis initially simply set by the operator.

Vice versa, it may be relevant to measure at least the conductivitydownstream the filtration unit (and preferably also the conductivityupstream the filtration unit) as soon as possible, i.e. as soon asstable conditions are reached or as soon as an estimate of suchconductivity in stable conditions may be performed.

This is due to the need of matching as much as possible the patientinitial plasma conductivity which is clearly affected/changed by thedifferent conductivity of the dialysis fluid circulating during thetreatment.

In order to make a first estimate of the plasma conductivity based onmeasured values, two embodiments are provided, which may be usedtogether or alternatively.

Firstly, the control unit 12 calculates the value of the initial plasmaconductivity, based on the measured initial parameter value of thedialysate (i.e. based on conductivity or concentration measurement ofdialysate on the filtration unit outlet) and on the correspondingparameter value of the dialysis fluid in the dialysis fluid supply line8 e.g. conductivity or concentration). During the start of the treatmentand particularly during circulating the dialysis fluid through thesecondary chamber 4 up to measuring the initial value of the parameterof the dialysate downstream of the secondary chamber used for thecalculating of the initial plasma conductivity, the dialysis fluidconductivity (or concentration) is kept substantially constant.

Just a single reliable measurement at the inlet and at the outlet of thedialyzer may be sufficient to have a preliminary (to be made moreaccurate) or an already final estimation of the PC.

From a general point of view, the control unit 12 is further configuredto calculate the plasma conductivity as a function of at least one ormore flow rates. The flow rates include the dialysate flow rate at theoutlet of the secondary chamber 4; in addition, the flow rates mayinclude the blood flow rate in the blood lines too.

Specifically, according to the first embodiment, the control unit 12 isconfigured to calculate the plasma conductivity using the followingformula:

$\begin{matrix}{\kappa_{p,1}^{\prime} = {\kappa_{0,{do}} + {\frac{Q_{do}}{Q_{Bset}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}} & (2)\end{matrix}$

The significance of the denotations above is given in the Glossary.

According to the second embodiment, the control unit 12 is configured tocalculate the plasma conductivity using the following formula:

$\kappa_{p,1}^{''} = {\kappa_{0,{di}} + {\frac{Q_{do}}{K_{u}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}$

The significance of the denotations and constants above is given in theGlossary.

It is worth to underline that during the above described calculation ofthe initial plasma conductivity (formulas (2) and (3)), the dialysisfluid circulates through the secondary chamber maintaining the dialysisfluid parameter value substantially constant.

According to first estimate, k_(p,1) may be found after approx. 6 to 10minutes after treatment start.

Of course, both formulas (2) and (3) for estimation of plasmaconductivity may be iteratively applied, meaning that the newlycalculated estimate of PC (k_(p,1)) is imposed to the dialysis fluid anda new estimate again calculated after taking measures of theconductivity at the inlet and outlet of the filter as soon as stableconditions are reached.

Of course, in case of iteration of anyone of the above calculationsaccording to formulas (2) or (3), after the first plasma conductivityestimation, the dialysis fluid parameter value is changed since thenewly calculated estimate of PC (k_(p,1)) is imposed to the dialysisfluid, meaning that the conductivity of the dialysis fluid is changed.This however does not impact on the fact that the first calculationaccording to formulas (2) and (3) is made without a change in theconductivity of the dialysis fluid.

The dialysis fluid sodium concentration correspondent to k_(p,pre) isthen determined.

The resulting dialysis fluid sodium concentration applied, c_(di,Na),k_(p,pre), would correspond to implement an isoconductive dialysis.

However, since an isotonic or isonatremic or isonatrikalemic dialysis isto be in principle applied, this sodium value may be adjusted with aproper adjustment factor (depending on the choice to apply isotonic,isonatremic or isonatrikalemic dialysis).

In respect to the above mentioned treatments, it is relevant to note thefollowing.

An isonatremic dialysis may in general terms be considered as atreatment where the sodium concentration in the extracellular fluid ofthe patient is maintained stable or undergoes reduced variationsthroughout treatment.

It is however worth noting that tonicity is determined by the particlesthat are osmotically active.

Actually, the dialysis fluid (and the plasma) contains a multitude ofsubstances that influence tonicity/osmolality, not just sodium, even ifthis is the main determinant of serum osmolality.

Hence, an isotonic dialysis may be considered as a dialysis where thetonicity of the fluids in the patient is maintained stable throughouttreatment or undergoes reduced variations throughout treatment. Thiswould be achieved by maintaining the tonicity of the dialysis fluidsubstantially equal to the tonicity of the extracellular fluidthroughout treatment. In this case, the tonicity of the dialysis fluiddoes not change pre- to post-filtration unit 2.

An isonatrikalemic dialysis, may in general terms be considered as atreatment where the sum of sodium and potassium concentrations in thepatient extracellular fluid is maintained stable or undergoes reducedvariations throughout treatment (in this case, the sum of sodium andpotassium concentrations of the dialysis fluid does not change pre- topost-filtration unit 2). Considering that a patient shall lose a certainamount of potassium during treatment, the isonatrikalemic condition maybe maintained with a proportional increase in serum sodiumconcentration. In general, a patient has a potassium overload which isto be reduced; at the same time, in an isonatrikalemic dialysis it isdesired not to change too much the tonicity of the blood, thereforepotassium is reduced, but the sum of sodium and potassium is keptconstant (i.e. plasma sodium slightly increases).

An isoconductive dialysis may in general terms be considered as adialysis treatment maintaining the conductivity of the dialysis fluidequal to the conductivity of the extracellular fluid, which in this caseis represented by the plasma conductivity.

The plasma conductivity (PC,

_(p)) is the conductivity at which the dialysis fluid conductivity isnot changed during its passage through the dialyzer. Then theconductivities upstream and downstream the filtration unit 2 are equal:

_(di)=

_(do).

In case of an isotonic or isonatremic or isonatrikalemic treatment is tobe performed, the mentioned adjustment factor is calculated based onmolar conductivities, dialysis fluid composition and the best estimateof plasma water composition as will better emerge from the followingdescription. The best estimate of plasma water composition may bederived from literature, or may be based on statistical prepared values,or test of patient, or obtained with direct lab measurements made beforethe treatment.

According to an aspect, the control unit 12 receives a valuerepresentative of a parameter of the blood in said blood lines 6, 7. Theblood parameter may be the plasma conductivity or a plasmaconductivity-related parameter.

In particular, the control unit 12 may be programmed for calculating theplasma conductivity, for example executing the method previouslydisclosed or, alternatively using known methods such as those describedin EP 2377563.

Alternatively, the control unit 12 directly receives as an input theplasma conductivity. For example, the physician or the nurse may receivea lab analysis and may provide the datum to the machine through the userinterface of the dialysis monitor; the control unit 12 is programmed forstoring in a memory the plasma conductivity to be used for the followingdialysis fluid parameter regulation.

Finally, the plasma conductivity may be directly measured in vivo by themonitor before starting the treatment session using a proper plasmaconductivity sensor.

The control unit 12 is generally configured for setting a value of afirst parameter for the dialysis fluid in the dialysis supply line 8 ata set point.

The first parameter for the dialysis fluid is chosen between aconductivity of the dialysis fluid, a conductivity-related parameter ofthe dialysis fluid, a concentration of a substance in the dialysis fluidand a concentration-related parameter of a substance in the dialysisfluid.

Depending on the specific dialysis monitor, the sodium content (or thecontent of more than one electrolyte) may be regulated in the dialysisline. Alternatively, the control parameter may be the overallconductivity of the dialysis fluid.

The setting of the value of the first parameter in the dialysis fluid(which is hereinafter generally identified as sodium concentration setpoint in the dialysis fluid with no limiting effect) may include a firstand a second adjustment step.

In the first adjustment step, a proposed value for the first parameteris determined (e.g. a proposed sodium concentration value iscalculated).

In the second adjustment step, a set value for the first parameter iscalculated as a function of the proposed value (e.g. a set value forsodium concentration in the dialysis fluid is calculated starting fromthe proposed value).

The first adjustment step includes the sub-step of calculating thesodium concentration set point as a function of a main contribution termbased on/function of the plasma conductivity and as a function of anadjustment contribution term, i.e. a term which takes into account thetransport driving gradient of certain specific substances.

The calculation is an algebraic sum of at least the main contributionterm c_(di,Na,)

_(p,pre) and the adjustment contribution term c_(di,Na,adj) according tothe following general formula:

c _(di,Na,set) =c _(di,Na,)

_(p,pre) +c _(di,Na,adj)   (4)

In order to obtain a dialysis fluid sodium implementing a certain kindof dialysis, i.e. C_(di,Na,set), an adjustment factor C_(di,Na,adj)needs to be applied to make the dialysis fluid matching a certainspecific concentration of the plasma.

C_(di,Na,)

_(p,pre) is the dialysis fluid concentration of sodium at isoconductivestate, i.e. when the dialysis fluid conductivity

_(di) matches the estimated pre-dialysis plasma conductivity

_(p,pre).

Though not essential since a calculation may be made based onconductivities too, the main contribution term and the adjustmentcontribution term are dimensionally concentrations of a substance (e.g.sodium) in a fluid.

The adjustment contribution term is the sodium concentration set pointadjustment relative to an isoconductive state to provide a specifictreatment which may be, for example, chosen in the group includingisotonic dialysis, isonatremic dialysis and isonatrikalemic dialysis.

The Applicant has understood that certain specific substances, namelybicarbonate, potassium, acetate, and citrate have a major effect whichshould be taken into account when it is desired to run a purelyisotonic, or isonatric, or isonatrikalemic dialysis treatment. Indeed,an isoconductive dialysis (i.e. a dialysis maintaining the conductivityof the dialysis fluid equal to the conductivity of the extracellularfluid, which in this case is represented by the plasma conductivity—asdefined, plasma conductivity PC,

_(p) as the conductivity at which the dialysis fluid conductivity is notchanged during its passage through the dialyzer so that the pre-dialyzerand the post-dialyzer conductivities are equal:

_(di)=

_(do)) causes an overload of sodium in the patient.

To avoid overloading at least the effect of the above substances must betaken into duly consideration. Of course other substances play a role,such as lactate, magnesium, and calcium.

Furthermore, the difference in concentration between same substances inthe blood and in the dialysis fluid influences, as well, the sodiumoverload in case of isoconductive treatments.

Given the above, the Applicant also realized that in calculating theadjustment contribution term, certain parameters having a weight indetermining the overload of sodium are known and depends on the machinedressing (e.g. used concentrates) or on the prescription for the patient(e.g. dialysate flow rate). Other parameters depend on the patientundergoing the treatment and therefore may be either directly measured(e.g. lab analysis) or estimated (e.g. based on large population numbersor patient history).

Since isoconductive dialysis causes sodium overload, the adjustmentcontribution term generally assumes a negative value, i.e. reduces theset point concentration of sodium in the dialysis fluid calculated forisoconductive treatment.

In order to obtain a dialysis fluid sodium implementing isotonicdialysis, i.e. c_(di,Na,set,isotonicr) an adjustment factorc_(di,Na,isotonic.adj) needs to be applied to make the dialysis fluidmatching the tonicity of the plasma:

c _(di,Na,set,isotonic) =c _(di,Na,)

_(p,pre) +c _(di,Na,isotonic,adj)   (5)

where:

$\begin{matrix}{c_{{di},{Na},{isotonic},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\left( {M_{\kappa_{KCl}} - M_{\kappa_{NaCl}}} \right)\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)} + {\frac{Q_{do}}{K_{u}}\left( {\kappa_{{rest}\; 1} + \kappa_{{rest}\; 2}} \right)}} \right)}} & (6)\end{matrix}$

The significance of the denotations and constants above is given in theGlossary.

Factor k (namely, k_(rest1), k_(rest2) and k_(rest3)—see also thefollowing formulas (10) and (11)) defines the effect on the conductivitydue to other components in the dialysis fluid different from thecomponents already treated and included in the respective formula. Thus,the effect of salts containing calcium, magnesium, lactate, phosphate,and sulphate, but also glucose and urea, may have upon the conductivity.The effect created by these components is most often small, and does notvary considerably between the dialysis treatments.

In order to obtain a dialysis fluid sodium implementing isonatremicdialysis, i.e. c_(di,Na,set,isoNa), an adjustment factorc_(di,Na,isoNa.adj) needs to be applied to make the sodium concentrationof dialysate out from the dialyzer matching the sodium concentration ofdialysis fluid at the inlet of the dialyzer:

c _(di,Na,set,isoNa) =c _(di,Na,)

_(p,pre) +c _(di,Na,isoNa,adj)   (7)

where:

$\begin{matrix}{c_{{di},{Na},{isoNa},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}{M_{\kappa_{KCl}}\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)}} + {\frac{Q_{do}}{K_{u}}\kappa_{{rest}\; 3}}} \right)}} & (8)\end{matrix}$

The significance of the denotations and constants above is given in theGlossary.

In order to obtain a dialysis fluid sodium implementing isonatrikalemicdialysis, i.e. c_(di,Na,set,isoNa+K), an adjustment factorc_(di,Na,isoNa+K.adj) needs to be applied to make the sum of sodium andpotassium concentrations of dialysate out from the dialyzer matching thecorresponding sum of concentrations of dialysis fluid at the inlet ofthe dialyzer:

c _(di,Na,set,isoNa+K) =c _(di,Na,)

_(p,pre) +c _(di,Na,isoNa+K,adj)   (9)

where:

$\begin{matrix}{c_{{di},{Na},{{isoNa} + K},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\left( {M_{\kappa_{KCl}} - M_{\kappa_{NaCl}}} \right)\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)} + {\frac{Q_{do}}{K_{u}}\kappa_{{rest}\; 3}}} \right)}} & (10)\end{matrix}$

The significance of the denotations and constants above is given in theGlossary.

Of course, different formulas including one or more of the substancesabove stated may be alternatively used.

Once the proposed value for sodium concentration in the dialysis fluidis calculated (e.g. by Eqs. 5, 7 or 9), the control unit 12 may eitherdirectly use the calculated proposed value for properly regulating theconductivity or the concentration of the substance in the fresh dialysisfluid or may apply for the second adjustment step.

Indeed, for a big patient population, the average pre-dialysis plasmasodium concentration is approximately 138 mmol/l. However, patients mayhave pre-dialysis plasma sodium in the range 130-143 mmol/l (or evenlower or higher); moreover, patient plasma sodium vary considerably,both between patients and within a single patient.

The second adjustment step may be simply an additional offset that theoperator may manually input (or select from pre-stored values).

Indeed, in order to have a further degree of freedom for (e.g. sodiumset) adjustment, before applying it to the remainder of the treatment,any additional offset may be applied. This additional offset may bedifferent depending on the dialysis treatment type.

For example, the physician may modify the sodium concentration set pointincreasing or decreasing the sodium setting by e.g. 1 or 2 mM.

In a situation highly deviating from the mentioned average pre-dialysisplasma value, running an isotonic, isonatremic or an isonatrikalemictreatment may not be the best treatment option.

In these and other situations, it may be desirable to possibly apply afurther adjustment factor or offset to the proposed value

_(prop.value); c_(prop.value) of the first parameter for the dialysisfluid.

Notably, the proposed value

_(prop.value); C_(prop.value) Of the first parameter is eithercalculated by the control unit 12, for example in accordance with thepreviously described steps or is received as an input, e.g. the nurse orthe physician may directly input the proposed value into the apparatusreceiving said value from a lab measurement or from previous treatmentsessions, for example.

Moreover, the proposed value

_(prop.value); c_(prop.value) of the first parameter may be either aconductivity value

_(prop.value) for the dialysis fluid or a concentration valuec_(prop.value) for a substance, which might be sodium c_(Na,prop.value)and/or another ionic substance contained in the dialysis fluid.

In FIGS. 2 to 7, the specific examples refer to sodium concentration,however it is clear that the same examples (same kind of correctivefunctions) may be equally applied to any other substance (e.g.potassium) or to conductivity as well.

In case the first parameter is the concentration of at least a substancein the dialysis fluid (e.g. sodium), the proposed value c_(prop.valee)for the first parameter may be the substance concentration set point forrunning a pure isotonic dialysis or pure isonatremic dialysis or pureisonatrikalemic dialysis. In other terms, c_(prop.value) may becoincident with i.e. c_(di,Na,set,isoNa) (dialysis fluid sodiumconcentration implementing isonatremic dialysis), orc_(di,Na,set,isoNa+K) (dialysis fluid sodium concentration implementingisonatrikalemic dialysis), or c_(di,Na,set,isotonic) (dialysis fluidsodium concentration implementing isotonic dialysis).

Alternatively, the proposed value c_(prop.value) for the first parametermay be the substance concentration set point for running anisoconductive dialysis, i.e. c_(di,Na,)

_(p,pre) . In this case, the substance concentration set point forrunning an isoconductive dialysis may be calculated according to themethod disclosed in the previous description or calculated according tothe method described, for example, in EP 547025 or in EP 920877.

In case the first parameter is the dialysis fluid conductivity, theproposed value

_(prop.value) for the first parameter is correspondingly theconductivity set point for running an isotonic dialysis or isonatremicdialysis or an isonatrikalemic dialysis or an isoconductive dialysis, asthe case may be.

Once the proposed value

_(prop.value); c_(prop.value) for the first parameter is obtained (i.e.calculated or received), the control unit 12 determines a set value

_(setvalue); c_(setvalue) for the first parameter as a function of theproposed value

_(prop.value); c_(prop.value) for the first parameter.

The basic idea is to modify the dialysis fluid set point, so that ingeneral it is not directly equal to the estimated sodium concentrationfor isotonic, isonatremic, isonatrikalemic (or isoconductive) treatment.

A first exemplificative approach, consist in determining a set value

_(setvalue); c_(setvalue) for the first parameter as a linear functionof the proposed value

_(prop.value); c_(prop.value) for the first parameter.

In this respect, the control unit 12 may be configured to determine theset value

_(setvalue); c_(setvalue) for the first parameter as a function of thedifference between the proposed value

_(prop.value); c_(prop.value) for the first parameter and apredetermined value

_(pivot); c_(pivot) for the first parameter.

The predetermined value

_(pivot); c_(pivot) is chosen so that the linear equation “pivots”around a suitable sodium concentration (or dialysis fluid conductivity).

In case the first parameter is a concentration, this predetermined valuemay be a constant value comprised between 120 mmol/l and 150 mmol/l, inparticular comprised between 130 mmol/l and 143 mmol/l and in even moredetail between 134 mmol/l and 140 mmol/l. In more detail thepredetermined value c_(pivot) may be the average pre-dialysis plasmasodium concentration for a large population or the average pre-dialysisplasma sodium concentration for an individual patient (e.g. 138 mmol/l).

It is noted that for a proposed value

_(prop.value); c_(prop.value) equal to the predetermined value

_(pivot); c_(pivot), the correspondingly calculated set value

_(setvalue); c_(setvalue) is equal to the predetermined value

_(pivot); c_(pivot) too.

Notably, the operator may manually enter the predetermined value

_(pivot); c_(pivot); alternatively, the predetermined value

_(pivot); c_(pivot) may be pre-set in the dialysis machine and possiblyproposed to the operator for being confirmed or altered (if necessary).

In a first embodiment, the control unit 12 is configured to determinethe set value

K_(setvalue); c_(setvalue) for the first parameter as a function of theweighted difference between the proposed value ƒ_(prop.value);c_(prop.value) for the first parameter and the predetermined value forthe first parameter

_(pivot); c_(pivot), particularly according to any of the followingmathematical relationships (referring to concentration or conductivity):

c _(setvalue)=β·(c _(prop.value) −c _(pivot))+c _(pivot)

or

_(setvalue)=β·(

_(prop.value)+

_(pivot))+

_(pivot)

wherein β is the slope of the linear function (constant value) chosen inthe range 0 to 1: 0<β<1.

A reasonable value for β in order to obtain proper correction of highlydeviating values is included in the range between 0.3 to 0.8, i.e.0.3≤β≤0.8.

Notably, the operator may manually enter the β value; alternatively, thevalue may be pre-set in the dialysis machine and possibly proposed tothe operator for being confirmed or altered (if necessary).

FIG. 2 illustrates a diagram showing the effect of applying the proposedadjustment to the proposed value for the sodium concentration.

Continuous line with β=1 (no adjustment) correspond not to apply anyadjustment factor: in this case c_(Na,setvalue)=c_(Na,prop.value).

FIG. 2 additionally illustrates two possible linear functions (dashedlines) according to embodiments of the invention and differing for therespective slope. As it can immediately perceived, the lower is theslope β the higher is the adjustment factor applied to the proposedvalue, particularly at the highest deviation from the predeterminedvalue C_(Na,pivot) (which is fixed at 138 mmol/l in the figures.

In certain situations it is advantageous to set upper and/or lowerlimits for the set value of the first parameter, which might not beexceeded. This is done either for safety reasons (danger for thepatient) or for technical reasons (e.g. the used concentrates do notallow preparing certain dialysis fluid compositions).

In such cases, the apparatus may simply signal an abnormal situation ormay however set safe or technically reachable limits.

FIG. 3 is an example according to what above described.

In case the set value

_(setvalue); c_(setvalue) for the first parameter determined by thecontrol unit 12 exceeds an upper limit for the first parameter (141mmol/l in the example of FIG. 3), the set value

_(setvalue); c_(setvalue) is set at a value equal to the upper limititself.

In case the calculated set value

_(setvalue); c_(setvalue) for the first parameter determined by thecontrol unit 12 is lower than a lower limit for the first parameter (134mmol/l in the example of FIG. 3), the set value

_(setvalue); c_(setvalue) is set at a value equal to the lower limititself.

In other terms, FIG. 3 discloses an example according to which the setvalue c_(Na,setvalue) is linearly adjusted (β=0.7 or β=0.5) inside aninterval comprised between upper and lower limits, and the set valuec_(Na,setvalue) is set at the respective limit value if the proposedvalue c_(Na,prop.value) is lower or exceeds the respective limit.

According to the examples of FIGS. 2 and 3, in the linear interval ofadjustment function, the set value

_(setvalue); c_(setvalue) differs from the proposed value

_(prop.value); c_(prop.value) by a delta; said delta increases(linearly) as the proposed value

_(prop.value); c_(prop.value) moves away from a predetermined value

_(pivot); c_(pivot) for the first parameter.

In the example of FIG. 4, a different function is used to achieve softerset values at the curve limits. In particular, the delta increases asthe proposed value

_(prop.value); c_(prop.value) moves away from a predetermined value

_(pivot); c_(pivot) for the first parameter.

In more detail, the control unit 12 determines the set value

_(setvalue); c_(setvalue) for the first parameter as a nonlinearfunction of the proposed value

_(prop.value); c_(prop.value) for the first parameter; as it may beperceived looking at FIG. 4, the used corrective function has a slopethat varies between points (non-constant) at least in correspondence ofthe curve limits so as to define soft maximum or minimum values. Inparticular, at least outside a central interval, the slope decrease asthe proposed value

_(prop.value); c_(prop.value) moves away from the predetermined value

_(pivot); c_(pivot).

Of course, as for the case of FIG. 3, also in the example of FIG. 4upper and lower limits might be set and the set value

_(setvalue); c_(setvalue) set to one of the limits.

Notably, the operator may manually enter the upper and/or lower limit;alternatively, the limits may be pre-set in the dialysis machine andpossibly proposed to the operator for being confirmed or altered (ifnecessary).

A combination of the linear and nonlinear function for adjusting theproposed value is also within the scope of the present invention. Insuch case, the adjustment may be linear in an interval in the closeproximity of the predetermined value

_(pivot); c_(pivot) and nonlinear outside said interval (i.e. close tothe extremities of the curve).

Additionally, other more complex functions may be used to adjust the setvalue

_(setvalue); c_(setvalue).

For example, a combination of linear and nonlinear functions as per FIG.5.

In this particular embodiment, different functions may be used dependingon the proposed value in input, for example according to the followingsystem of equations:

c _(Na,prop.value)≤135 c _(Na,setvalue)=const

135<c _(Na,prop.value)<137 c _(Na,setvalue)=β₁·(c _(Na,prop.value) −c_(Na,pivot,1))+c _(Na,pivot,1)

137≤c _(Na,prop.value)≤139 c _(dNa,setvalue) =c _(Na,prop.value)

139<c _(Na,prop.value)<140 c _(Na,setvalue)=β₂·(c _(Na,prop.value) −c_(Na,pivot,2))+C _(Na,pivot,2)

c _(Na,prop.value)≥140 c _(Na,setvalue) =f(c _(Na,prop.value) ^(1/2))

As can be understood, for proposed values close to a selected averagedialysis sodium content (e.g. 138 mmol/l), treatment is kept purelyisotonic (or isonatremic or isonatrikalemic), i.e. the proposed value isnot modified (see interval from 137 mmol/l to 139 mmol/l).

A linear adjustment is applied immediately outside this interval;according to the above system, in the interval from 135 mmol/l to 137mmol/l the proposed value (low sodium content) is slightly increasedaccording to slope β₁ whose value is different from 1 (e.g. β₁=0.5).

In the upper interval from 139 mmol/l to 140 mmol/l the proposed value(high sodium content) is slightly decreased according to slope β₂ whosevalue is different from 1 (e.g. β₂=0.5).

In the lowest interval (proposed value lower than 135 mmol/l), the setvalue is constantly set equal to the minimum threshold, i.e.c_(Na,setvalue)=135 mmol/l.

In the highest interval (proposed value higher than 140 mmol/l), the setvalue is highly decreased (adjustment is non-linear), and for example isdecreased of a square factor, i.e. the set value is a function of√{square root over (c_(Na,prop.value))}.

Of course different equations or system of equations might be used toproperly take into account the upper and lower deviations from thenormal plasma sodium average level in the population.

As apparent, for at least an interval of proposed values for the firstparameter, the general principle is to determine the set value

_(setvalue); c_(setvalue) so that the set value

_(setvalue); c_(setvalue) differs from the proposed value

_(prop.value); c_(prop.value) by a delta and said delta depends on adistance of the proposed value

_(prop.value); c_(prop.value) from a predetermined value

_(pivot); c_(pivot) for the first parameter.

In such interval, the control unit 12 is in detail configured todetermine the set value so that the set value

_(setvalue); c_(setvalue) is different from the proposed value

_(prop.value); c_(prop.value), and so that distinct set values aredetermined from distinct proposed values; in other terms, for at leastthe interval of proposed values for the first parameter, an adjustmentdelta is applied to each proposed value falling into the interval and toeach different proposed value, a different adjustment delta is applied(generally adjustment increases moving away from the predetermined value

_(pivot); c_(pivot)).

According to FIGS. 2 and 4, said interval of proposed values for thefirst parameter (for which the set value

_(setvalue); c_(setvalue) is different from the proposed value

_(prop.value); c_(prop.value), and distinct set values are determinedfrom distinct proposed values) includes the whole range of possibleproposed values.

According to FIG. 3, the same interval of proposed values for the firstparameter includes, for β=0.5, the interval from 130 mmol/l to 144mmol/l; for β=0.7, the interval is included in the range from (about)132.3 mmol/l to (about) 142.3 mmol/l.

According to FIG. 5, the same interval may be either in the range from135 mmol/l to 137 mmol/l, or for the proposed values higher than 139mmol/l.

The ‘interval’ is intended as a continuous single interval of values andshould include at least two or more contiguous proposed values.

In this respect also FIG. 6 shows an embodiment of the present inventionaccording to the claims.

FIG. 6 is a diagram of proposed values and set values in which theillustrated function designed to convert the proposed value to the setvalue for the sodium concentration is peculiar.

Indeed, a step-wise function has been used which approximates one of thelinear functions of FIG. 2, with β<1.

As can be seen, for a close series of proposed values (under the samestep), the set values are equal; the set values then discretely increasestep-wise at the progressive increase of the proposed values.

However, also the depicted step-wise function includes at least aninterval in which the control unit 12 is configured to determine the setvalue not only so that the set value

_(setvalue); c_(setvalue) is different from the proposed value

_(prop.value); c_(prop.value), but also so that distinct set values aredetermined from distinct proposed values.

Indeed, the interval including the last proposed value of a step and theimmediately following proposed value corresponding to the next step arean interval for which the set value

_(setvalue); c_(setvalue) is different from the proposed value

_(prop.value); c_(prop.value), and the two distinct set values aredetermined from two correspondingly distinct proposed values.

The enlarged view of FIG. 6a illustrates a first proposed valuec_(Na,prop.value1) which, according to the applied adjustment function,originates a set value of (about) 134.2 mmol/l and the immediatelyfollowing proposed value c_(Na,prop.value2) originates a set value of(about) 135.8 mmol/l. At least for the continuous interval constitutedby c_(Na,prop.value1) and c_(Nprop.value2) the above conditions (the setvalue

_(setvalue); c_(setvalue) is different from the proposed value

_(prop.value); c_(prop.value), and distinct set values are determinedfrom distinct proposed values) are fulfilled.

Notwithstanding the fact that FIGS. 1 to 5 show continuous correctivefunctions, in the actual implementation the functions may beapproximated by means of discrete steps as described for FIG. 6 an asshown in FIG. 7, for example.

FIG. 7 illustrates a possible approximation of the linear function ofFIG. 1 (β=0.7) through a plurality of discrete and small steps. The sameapproximation may be adopted in respect to any other corrective functionsuch as those of FIGS. 3 to 5.

Once the set value

_(setvalue); c_(setvalue) for the first parameter is calculated, thesame set value is stored in a memory and proposed (e.g. visualized) tothe operator.

The operator may then manually set the value for the first parameter orconfirm to the apparatus that the set value

_(setvalue); c_(setvalue) is acceptable and has to be set asprescription value.

Of course, the operator confirmation may be optional and the controlunit may use the set value

_(setvalue); c_(setvalue) for properly and automatically driving theapparatus.

In this respect, the control unit 12 drives the regulating means forregulating the conductivity or the concentration of the substance in thefresh dialysis fluid and sets the parameter value for the dialysis fluidin the dialysis fluid supply line 8 at the calculated set point (setvalue

_(setvalue); c_(setvalue)).

In particular, the control unit 12 may be programmed to allow selectionof at least one treatment mode chosen in the group including isotonicdialysis, isonatremic dialysis and isonatrikalemic dialysis, the controlunit configured to drive the regulating means as a function of thecalculated set value

_(setvalue); c_(setvalue) and of the chosen treatment mode to set eithera desired dialysis fluid inlet conductivity or a desired dialysis fluidinlet substance (e.g. sodium) concentration.

Furthermore, the control unit 12 may be programmed to keep the desireddialysis fluid inlet conductivity (and/or sodium concentration)substantially constant throughout the remainder of the treatment.

Hence, the output of the described task is a new value for sodiumconcentration in the dialysis fluid, which is used as sodium set valuefor the regulating means (i.e. concentrate dosing system) when (e.g.isotonic) dialysis is active.

Advantageously, the changes to sodium set value will not affect thebicarbonate set value, which remains the one set by the operator.

After the setting of the adjusted sodium set point for the (e.g.isotonic) treatment, the plasma conductivity may be furthercalculated/monitored using common procedures, such as those described inpatents EP 547025 or in EP 920877 to monitor PC throughout thetreatment.

1-16. (canceled)
 17. An apparatus for extracorporeal blood treatmentcomprising: a filtration unit having a primary chamber and a secondarychamber separated by a semi-permeable membrane; a blood withdrawal lineconnected to an inlet of the primary chamber; a blood return lineconnected to an outlet of the primary chamber, said blood lines beingfor connection to a patient cardiovascular system; a dialysis supplyline connected to an inlet of the secondary chamber; a dialysis effluentline connected to an outlet of the secondary chamber; a producer forpreparing a dialysis fluid connected to said supply line and comprisinga regulator for regulating the composition of the dialysis fluid; and acontrol unit connected to the regulator and programmed for obtaining aproposed value of a first parameter for the dialysis fluid in thedialysis supply line, the first parameter being one of a conductivityfor the dialysis fluid, a conductivity-related parameter for thedialysis fluid, a concentration of at least a substance for the dialysisfluid, a concentration-related parameter of at least a substance for thedialysis fluid, said control unit being configured for determining a setvalue for the first parameter as a function of the proposed value forthe first parameter, wherein, for at least an interval of proposedvalues for the first parameter, the control unit is configured todetermine the set value so that the set value is different from theproposed value, and so that distinct set values are determined fromdistinct proposed values.
 18. The apparatus according to claim 17,wherein, for at least said interval of proposed values for the firstparameter, the control unit is configured to determine the set value forthe first parameter as a linear function of the proposed value for thefirst parameter.
 19. The apparatus according to claim 17, wherein, forat least said interval of proposed values for the first parameter, thecontrol unit is configured to determine the set value for the firstparameter as a function of the difference between the proposed value forthe first parameter and the predetermined value for the first parameter:c _(setvalue) =f[(c _(prop.value) −c _(pivot))]or

_(setvalue) =f[(

_(prop.value)−

_(pivot))], wherein c_(prop.value);

_(prop.value) is the proposed value for the first parameter in thedialysis fluid; c_(setvalue);

_(setvalue) is the set value for the first parameter in the dialysisfluid; c_(pivot);

_(pivot) is the predetermined value for the first parameter.
 20. Theapparatus according to claim 17, wherein, for at least said interval ofproposed values for the first parameter, the control unit is configuredto determine the set value for the first parameter as a function of adifference between the proposed value for the first parameter and apredetermined value for the first parameter according to the followingmathematical relationship:c _(setvalue)=β·(c _(prop.value) −c _(pivot))+c _(pivot)or

_(setvalue)=β·(

_(prop.value)−

_(pivot))+

_(pivot) wherein c_(prop.value);

_(prop.value) is the proposed value for the first parameter in thedialysis fluid; c_(setvalue);

_(setvalue) is the set value for the first parameter in the dialysisfluid; c_(pivot);

_(pivot) is the predetermined value for the first parameter; wherein βis a constant chosen in the range 0 to 1: 0<β<1.
 21. The apparatusaccording to claim 17, wherein for at least one predetermined value forthe first parameter, the control unit is configured to determine the setvalue so that the set value is equal to the proposed value.
 22. Theapparatus according to claim 17, wherein in case the proposed value forthe first parameter is lower than a lower limit for the first parameter,the set value is set to the lower limit and in case the proposed valuefor the first parameter exceeds an upper limit for the first parameter,the set value is set to the upper limit.
 23. The apparatus according toclaim 17, wherein the control unit is configured to determine the setvalue for the first parameter as a linear function of the proposed valuefor the first parameter in an interval including a predetermined valuefor the first parameter, the control unit being further configured todetermine the set value for the first parameter as a non-linear functionof the proposed value for the first parameter outside said interval. 24.The apparatus according to claim 17, wherein, for at least said intervalof proposed values for the first parameter, the control unit isconfigured to determine the set value for the first parameter so thatthe set value differs from the proposed value by a delta, said deltaincreasing as the proposed value moves away from a predetermined valuefor the first parameter.
 25. The apparatus according to claim 17,wherein, for at least said interval of proposed values for the firstparameter, the control unit is configured to determine the set value forthe first parameter so that the set value differs from the proposedvalue by a delta, said delta increasing linearly in magnitude as theproposed value moves away from a predetermined value for the firstparameter.
 26. The apparatus according to claim 17, wherein, outsidesaid interval of proposed values for the first parameter, the controlunit is configured to determine the set value for the first parameter asa nonlinear function of the proposed value for the first parameter, saidfunction having a slope that varies between points, in particular saidslope decreasing as the proposed value moves away from a predeterminedvalue for the first parameter.
 27. The apparatus according to claim 24,wherein said delta is positive if the proposed value is lower than apredetermined value for the first parameter and wherein said delta isnegative if the proposed value is higher than a predetermined value forthe first parameter.
 28. The apparatus according to claim 17, wherein,for at least said interval of proposed values for the first parameter,the control unit is configured to determine the set value for the firstparameter so that: the set value is lower than the proposed value if theproposed value is higher than a predetermined value for the firstparameter; the set value is higher than the proposed value if theproposed value is lower than the predetermined value for the firstparameter.
 29. The apparatus according to claim 17, wherein the firstparameter is the concentration of at least one substance in the dialysisfluid, said substance being sodium.
 30. The apparatus according to claim17, wherein the first parameter is the dialysis fluid conductivity. 31.The apparatus according to claim 17, wherein the control unit drives theregulator for regulating the conductivity or the concentration of atleast a substance in the dialysis fluid, the control unit setting thefirst parameter value for the dialysis fluid in the dialysis supply lineat the set value of the first parameter calculated by the control unit.32. The apparatus according to claim 17, wherein the control unit isconfigured for either calculating the proposed value for the firstparameter or receiving the proposed value as an input, said proposedvalue for the first parameter being the substance concentration setpoint or the conductivity set point for running an isotonic dialysis orisonatremic dialysis or an isonatrikalemic dialysis.
 33. the apparatusaccording to claim 17, wherein the control unit is configured forcalculating the proposed value for the first parameter as a function ofa main contribution term based on one of a plasma conductivity, a plasmaconductivity-related parameter, a concentration of at least a substancein the blood, a concentration-related parameter of at least a substancein the blood, and the control unit is additionally configured forcalculating the proposed value for the first parameter as a function ofan adjustment contribution term based on a concentration of at least asubstance in the dialysis fluid chosen in the group includingbicarbonate, potassium, acetate, lactate, citrate, magnesium, calcium,sulphate and phosphate.